We know from fossilized skulls that their brains were large – in fact, slightly larger than ours – but they tell us little about their neurology and development.
Scientists at the University of California San Diego have come up with an exciting and provocative way to answer this question. They have created blobs of brain tissue that have been genetically modified to carry a gene that belonged to Neanderthals and other archaic hominins, but not Homo sapiens.
Although the research is still in the very early stages, the researchers found that the Neanderthalized brain organoids caused significant changes in the way the brain is organized and wired.
“The question here is what makes us human,” said Alysson Muotri, professor and director of the stem cell program at the Institute for Genomic Medicine at the University of California San Diego School of Medicine.
“Why are our brains so different from other species, including our own extinct relatives?”
Neuroarchaeology
Muotri, who has worked on the project for eight years so far, calls his work “neuroarchaeology.”
“When you find a piece of bone or (charcoal) and you try to reconstruct how that society lived, what they did, how they were connected, you try to understand the mind. We do the same at the genetic level.”
The Neanderthalized brain organoids had a “popcorn shape” compared to the more round, more even shape of the modern human, Muotri said. His team also noted that the neurons in the organoids matured more quickly than modern human ones.
“The neurons in the archaic version of organoids, we see more activity in the very early stages than the modern human. We had absolutely not expected that.”
He said he had observed similar activity in his previous work on chimpanzee organoids.
“A baby chimpanzee can outsmart a newborn human by far. We need time to nurse our babies until they become independent. We don’t see that in other species. I think what we’re seeing here is something similar.”
However, Muotri stressed that this was speculative. Organoids are a long way from real brains. First, they lack connections to other organs.
“We don’t know how the human brain will behave with these archaic versions,” he said. “All of these differences that we see in the early stages could disappear because the brain can compensate.”
“But we do know that very early, subtle changes in brain development can affect the adult brain. Take, for example, the genes involved in autism.”
Gene editing with archaic material
We now know that many of us are a small portion of Neanderthals, with DNA containing traces of previous encounters between early modern humans and Neanderthals, who populated Europe and parts of Asia until about 40,000 years ago.
The UCSD team first compared the genomes of Neanderthals, Denisovans, and modern human populations to determine which genetic variants were not shared with our closest cousins.
“We asked what’s unique about us? We ended up with just 61 protein-coding genes that differ between modern and archaic humans,” Muotri said.
The team chose to focus on a gene known as NOVA1 because it is considered a “master regulator” of other genes that influence the early neurological development of modern humans. Changes to this gene have been linked to mental disorders such as schizophrenia and autism, he said.
The scientists then used CRISPR gene editing technology, which won the 2020 Nobel Prize in Chemistry, to swap the modern NOVA1 gene for the archaic version in human stem cells and persuade the stem cells to grow into organoids. .
“It’s an extremely difficult series of experiments,” said Grayson Camp, an assistant professor at the University of Basel in Switzerland who was not involved in the study.
“Organoids are difficult to control. If they had all the controls in there, you could believe that this change of one amino acid has a strong effect on brain development. That’s extraordinary.”
‘Not a magical variant that makes us human’
Obviously, such daring research is reserved.
Gene editing isn’t a perfect process, and inserting an archaic gene into human cells doesn’t reproduce what the Neanderthal genome actually was, said Tony Capra, an associate professor of epidemiology and biostatistics at Bakar Computational Health Sciences Institute at the university. of California, San Francisco.
“It is challenging to say that the results of the Neanderthal variant organoid necessarily reflect how Neanderthal brains evolved,” he said via email. Capra was not involved in the investigation.
“This change is being evaluated in the context of the human genome, so the archaic variant has a genetic background that doesn’t reflect what the Neanderthal genome was like.”
Nevertheless, Capra was enthusiastic about the research, which appeared in the journal Science on Thursday. However, he warned that “we should not expect there is one magical variety that has made us human.
“Most of the traits that make us modern humans compared to Neanderthals (or even chimpanzees) are very genetically complex,” Capra said. “Thousands of parts of our genome contribute to neurological development and cognition.”
He added, “Organoids are exciting because they allow us to test variants in more complex environments than single cells, but we will eventually need to ‘neandalize’ the organoid completely.”
Recent archaeological discoveries have suggested that Neanderthals had many of the same cognitive abilities as early modern humans, but like the fossils and stone artifacts, neuroarchaeology is unlikely to be able to provide definitive answers, Capra said.
“We will never be able to create the ecological and social context in which these individuals lived or these events took place. The environment is so essential to shape how genomes express themselves that we will always have to speculate,” he said.
“That said, I think we will learn a lot more about the bones and genomes in the years to come.”