In recent years, scientists have figured out how to grow blobs of hundreds of thousands of live human neurons that look — and act — something like a brain.
These so-called brain organoids have been used to study how brains develop into layers, how they begin to spontaneously make electrical waves and even how that development might change in zero gravity.
Now researchers are using these pea-size clusters to explore our evolutionary past to better understand the human brain. In a newly published study, scientists described how a gene likely carried by Neanderthals and our other ancient cousins triggered striking changes in the anatomy and function of brain organoids.
Researchers have studied how genetic mutations help give rise to disorders like autism. For example, organoids from people with Rett syndrome, a genetic disorder that results in intellectual disability and repetitive hand movements, grew few connections between neurons.
Katerina Semendeferi, a co-author of the study and an evolutionary anthropologist, and her colleagues found in previous work that in apes, neurons developing in the cerebral cortex stay close to each other, whereas in humans, cells can crawl away across long distances. "It's a completely different organization," she said.
But these comparisons stretch across a vast gulf in evolutionary time. Our ancestors split off from chimpanzees roughly 7 million years ago. For millions of years after that, our ancestors were bipedal apes, gradually attaining larger heights and brains and evolving into Neanderthals, Denisovans and other hominins.
It has been difficult to track the evolutionary changes of the brain along the way. Our own lineage split from that of Neanderthals and Denisovans about 600,000 years ago. After that split, fossils show, our brains eventually grew more rounded. But what that means for the 80 billion neurons inside has been hard to know.
Semendeferi and co-author Alysson Muotri teamed up with evolutionary biologists who study fossilized DNA. Those researchers have been able to reconstruct the entire genome of Neanderthals by piecing together genetic fragments from their bones. Other fossils have yielded genomes of the Denisovans, who split off from Neanderthals 400,000 years ago and lived for thousands of generations in Asia.
The evolutionary biologists identified 61 genes that may have played a crucial role in the evolution of modern humans. Each of those genes has a mutation that is unique to our species, arising sometime in the past 600,000 years.
Muotri and his colleagues wondered what would happen to a brain organoid if they took out one of those mutations, changing a gene back to the way it was in our distant ancestors' genomes. The difference might offer clues to how the mutation influenced our evolution.
"Our analysis made us say, 'Let's get a gene that changes a lot of other genes,' " Muotri said.
One gene looked particularly promising: NOVA1, which makes a protein that guides the production of proteins from a number of other genes. And humans have a mutation in NOVA1 not found in other vertebrates, living or extinct.
Muotri's colleague, Cleber Trujillo, grew a batch of organoids carrying the ancestral version of the NOVA1 gene.
The ancestral NOVA1 organoid had a noticeably different appearance, with a bumpy popcorn texture instead of a smooth spherical surface. "I said, 'OK, it's doing something,' " Muotri said.
The proportion of different types of brain cells was also different in the ancestral organoids. And the neurons in the ancestral organoids began firing spikes of electrical activity a few weeks earlier in their development than modern human ones did. But it also took longer for the electrical spikes to get organized into waves.
Other experts were surprised that a single genetic mutation could have such obvious effects on the organoids.
"It looks like the authors found a needle in a haystack based on an extremely elegant study design," said Philipp Gunz, a paleoanthropologist at the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany, who was not involved in the research.
Although the researchers do not know what the changes in the organoids mean for our evolutionary history, Muotri suspects that there may be connections to the kind of thinking made possible by different kinds of brains.
"The true answer is, I don't know," he said. "But everything that we see at very early stages in neurodevelopment might have an implication later on in life."