Hoping to learn what sets our brains apart from those of the Neanderthals, scientists have inserted a gene from our extinct cousins into human brain organoids — miniature versions of the real thing — and watched them grow in a lab dish.
Modern human DNA shares a large portion of its genetic code with archaic species like the Neanderthals and Denisovans, but the genes that aren’t shared might have been particularly important for evolution, according to researchers from the University of California, San Diego.
They used CRISPR genome-editing technology to replace a modern gene with an archaic Neanderthal variant within a human cortical organoid — a tiny 3D structure grown from a stem cell that mimics neurodevelopment of the cerebral cortex, though it doesn’t have the immense complexity of a human brain.
“My question was, what makes us uniquely humans, different from any other species including our extinct relatives?” said lead researcher Alysson Muotri. “The idea is the most novel aspect here.”
After comparing archaic DNA sequences with those of human populations today from around the world, Muotri and his team used the protein-coding gene NOVA1 for the study, published Thursday in Science. NOVA1 can be found within both modern and archaic DNA, but is one of only 61 genes with unique variants found in modern humans that aren’t shared with our archaic kin out of over 20,000 protein-coding genes.
NOVA1 has a managerial role as a master regulator of the developing nervous system and synapse formation. As a result, any changes from introducing the Neanderthal variant into the mini-brains would affect numerous other genes and be easier to spot. The pathways for the gene have been associated with conditions such as autism and schizophrenia.
Muotri’s team noticed changes in neurodevelopment after inserting the archaic gene in place of the modern one, but they’re careful not to qualify changes as better or worse. With the archaic NOVA1, neural synapses were firing at a faster rate, meaning the neurons would mature faster than modern human neurons do.
There was a reason modern humans evolved with the slower-developing gene, Muotri speculated. He pointed to the difference between humans and chimpanzees as an example: Baby chimpanzees develop much faster than humans. They can independently hunt and feed themselves early on while human parents are still caring for their child. But with a slower development in early stages, human brains become much more complex later on.
“Perhaps a good experiment would be to go to the chimpanzee and add the human version of that gene,” Muotri said. “Would that make the brain develop slower and would that chimp become more human-like in terms of cognition?”
Such an experiment will not be performed by Muotri. He hopes next to use the same genome-editing methods to test the effects of archaic variants of the 60 remaining modern-specific protein-coding genes. The results will form a catalog of genetic modifications in order to build a better understanding of the human brain’s evolutionary journey.
Muotri’s ambitions move faster than technical limitations — he’s wanted to do a study like this with Neanderthal genes since before technology like CRISPR and organoids were available. But using relatively new technology can also put qualifiers on research. CRISPR, he knows, is not perfect, and could unintentionally hit different regions of the genome. Organoids mimic brain development, but they’re not the same as a real brain in a real body and can’t be linked to specific behaviors. Still, he believes the study could have biomedical implications down the line.
“It’s a very useful model to move science forward and to get a better understanding of how the brain develops and how our genetic background affects that,” said Michael Gregory, who studies Neanderthal genetics in the brain at the National Institute of Mental Health and was not involved in this study.
Most scientific research on archaic DNA focuses on that which we have in common with the past, rather than the genetic code that separates us from it, according to Muotri. Genetic code shared with Neanderthals has been shown to provide advantages, such as in adapting to high altitudes, and disadvantages, such as susceptibility to diabetes.
“The opportunity to use technology similar to this with other genetic changes opens up a world of scientific possibilities,” said Gregory.
The study was performed on two cell lines from distinct neurotypical humans, and experts hope that more can be done on multiple cell lines from different ancestral, racial, and neurodiverse backgrounds to understand how the ancient gene variants impact different populations.
“The idea of what makes us human is an important question for anyone, whether you’re a scientist or not,” said Gregory. “And understanding how evolution has impacted and shaped us to make us who and what we are today is really important.”