In recent years, scientists have figured out how to grow spots from hundreds of thousands of living human neurons that look and work like a brain.
These so-called brain organoids have been used to investigate how brains develop in layers, how they spontaneously start making electric waves and even how the evolution can change into gravity. Now researchers are using these pea-sized bunches to explore our evolutionary past.
In a study published Thursday, a team of scientists describes how a gene probably carried by Neanderthals and our other ancient cousins caused striking changes in the anatomy and function of brain organs.
As dramatic as the changes are, scientists say it is too soon to know what these changes mean for the evolution of the modern human brain. “It’s more a proof of concept,” says Katerina Semendeferi, co-author of the new study and an evolutionary anthropologist at the University of California, San Diego.
Building on the findings, she and her co-author, Alysson Muotri, founded the UC San Diego Archealization Center, a group of researchers focused on studying organoids and making new ones with other ancient genes. “Now we have a start, and we can start investigating,” said dr. Semendeferi said.
Dr. Muotri started working with brain organoids more than a decade ago. To understand how Zika, for example, produces birth defects, he and his colleagues infected brain organoids with the virus, which prevented the organoids from developing their cortex-like layers.
In other studies, the researchers investigated how genetic mutations give rise to disorders such as autism. They transformed skin samples from volunteers with developmental disorders and transformed the tissue into stem cells. They then expanded those stem cells into brain organs. Organoids of people with Rett syndrome, a genetic disorder that results in intellectual disability and repetitive hand movements, have had few connections between neurons.
Dr. Semendeferi uses organoids to better understand the evolution of human brains. In previous work, she and her colleagues found that neurons that develop in the cerebral cortex stay close to each other in monkeys, while cells can hide over long distances. “It’s a very different organization,” she said.
But these comparisons span a huge gap in evolutionary time. Our ancestors tore off chimpanzees about seven million years ago. Millions of years later, our ancestors were bipedal monkeys that gradually reached greater heights and brains and evolved into Neanderthals, Denisovans, and other hominins.
It was difficult to detect the evolutionary changes of the brain along the way. Our own generation divided about 600,000 years ago from that of Neanderthals and Denisovans. After the split, fossil shows, our brains have finally become more rounded. But what that means for the 80 billion neurons inside is hard to know.
Dr Muotri and dr. Semendeferi collaborated with evolutionary biologists studying fossil DNA. Those researchers were able to reconstruct the entire genome of Neanderthal humans by combining genetic fragments from their bones. Other fossils have yielded genomes of the Denisovans, which tore off Neanderthals 400,000 years ago and lived in Asia for thousands of generations.
The evolutionary biologists have identified 61 genes that may have played a crucial role in the evolution of modern humans. Each of these genes has a mutation that is unique to our species, which originated for some time over the past 600,000 years and probably had a major influence on the proteins encoded by these genes.
Dr Muotri and his colleagues asked themselves what would happen to a brain organoid if they removed one of the mutations and turned a gene into the genomes of our ancestors. The difference between an ancestral organoid and an ordinary one may give an indication of how the mutation affected our evolution.
It took years before the scientists got the experiment off the ground. They struggled to find a way to exactly alter genes in stem cells before tempting them to turn into organoids.
After finding a successful method, they had to choose a gene. The scientists were worried that they would choose a gene for their first experiment that would do nothing to the organoid. They moderated how to increase their chances of success.
“Our analysis led us to say, ‘Let’s we get a gene that changes many other genes,'” Dr. Muotri said.
One gene on the list looked particularly promising in that regard: NOVA1, which makes a protein that then directs the production of proteins from a number of other genes. The fact that it is mainly active only in the developing brain has made it more attractive. And humans have a mutation in NOVA1 that is not found in other vertebrates, alive or extinct.
Dr. Muotri’s colleague, Cleber Trujillo, has grown a group of organoids that contain the ancestral version of the NOVA1 gene. After placing one under a microscope next to a normal brain organoid, he found dr. Muotri invited to watch.
The ancestral NOVA1 organoid had a strikingly different appearance, with a bumpy popcorn texture instead of a smooth spherical surface. “At that point, things started to go awry,” recalls Dr. Muotri. “I said, ‘OK, it’s doing something. ”
The ratio of different types of brain cells was also different in the ancestral organoids. And the neurons in the organoids of the ancestors began firing electrical activities a few weeks earlier than modern humans. But it also took longer before the electric nails organized into waves.
Other experts were surprised that a single genetic mutation could have such a clear effect on the organoids. They expected subtle shifts that would be difficult to observe.
“The authors appear to have 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 did not was not involved in the research.
Simon Fisher, the director of the Max Planck Institute for Psycholinguistics in the Netherlands, said the results had to come from a mixture of hard work and happiness. “There was certainly some serendipity,” he said.
Although the researchers do not know what the changes in the organoids mean for our evolutionary history, dr. Muotri that it may be related to the thinking made possible by different types of brains. “The real answer is, I do not know,” he said. “But everything we see in an early stage of neurodevelopment can have an implication later in life.”
In the new research center, dr. Semendeferi to perform careful anatomical studies on brain organoids and compare them with human fetal brains. This comparison will help to understand the changes that occur in the ancestral NOVA1 organoid.
And the team of dr. Muotri works through the list of 60 other genes to create more organoids that dr. Semendeferi can investigate. It is possible that the researchers may not be so happy because they were on their first try and will not see much difference with some genes.
“But others may be similar to NOVA1 and point to something new – some new biology that enables us to reconstruct an evolutionary path that has helped us become who we are,” said Dr. Muotri said.