Reengineering Life

Mini Neanderthal Brains Could Reveal the Origins of Psychiatric Disorders

The lab-grown organoids are helping us understand the modern brain

Brain organoids created by Alysson Muotri’s lab. Photo illustration; Image source: UC San Diego Health Sciences

Reengineering Life is a column from Future Human about the ways humans are using biology to reprogram our bodies and the world around us.

To study how the human brain evolved, scientists have relied on fossilized skulls from our ancient ancestors. These have given us clues about how we differ from our predecessors — that Neanderthal brains were more elongated than our modern ones, for instance — but they can tell only so much. Now, tiny blobs of lab-grown tissue that resemble Neanderthal brains may be able to help fill in some of the gaps.

Researchers at the University of California, San Diego, used stem cells to create miniature brains containing DNA from Neanderthals, our closest human relatives who died out around 40,000 years ago. The research revealed that a genetic variant harbored by Neanderthals led to striking changes in the organoids, suggesting the gene played a major role in the development of the modern human brain. The findings were published on February 12 in the journal Science.

No bigger than a pea, these so-called brain organoids could help scientists understand how our brains evolved to become so sophisticated. They could also shed light on how brain disorders like depression, anxiety, autism, and schizophrenia arose.

“Our hypothesis is that the sophistication of the human brain came with an evolutionary trade-off,” senior author Alysson Muotri, PhD, a neuroscientist at the University of California San Diego School of Medicine, tells Future Human. “The more sophisticated our brains, the higher the probability or the susceptibility for things to go wrong.”

While there’s growing evidence that animals may suffer from anxiety and depression and that some monkeys exhibit autism-like symptoms, schizophrenia seems uniquely human. Muotri’s lab is interested in finding out the biological underpinnings behind why humans are so susceptible to schizophrenia and other psychiatric and neurodevelopmental disorders.

A 2016 study suggested that schizophrenia is a modern development, one that emerged after humans diverged from Neanderthals. Other studies have found links between Neanderthal genes — many of us harbor between 1% to 2% of Neanderthal DNA — and the risk of depression and addiction. (My colleague Dana Smith at Elemental recently wrote about the various theories that explain why our brains evolved to be depressed.)

“I think reconstructing the evolutionary path that increases the complexity of the human brain will allow us to understand how those diseases became so frequent for us,” Muotri says.

To create the organoids, Muotri and his team first compared the genomes of modern humans to those of Neanderthals and Denisovans, another group of early hominids that split off from Neanderthals 400,000 years ago. The researchers were looking for genetic differences that could explain how modern humans evolved. They found 61 protein-coding genes that differ between us and our ancestral relatives. From there, they looked at genes involved in early brain development and narrowed in on one in particular: NOVA1, known to be a master regulator that affects the expression of other genes.

Muotri and his team then took skin cells from a “neurotypical” person — someone who doesn’t have neurodevelopmental disorders — and transformed them into stem cells, which have the ability to specialize into any cell type. They then used CRISPR gene editing to bestow the stem cells with the archaic variant of NOVA1 found in Neanderthals. Using substances known as growth factors, they coaxed the stem cells into neurons, which after months formed into tiny three-dimensional balls of brain tissue.

Neanderthal-like brain organoids (left) have a different shape than modern human brain organoids (right). Image: UC San Diego Health Sciences

Compared to organoids with the modern-day version of NOVA1, the ones with the Neanderthal variant looked noticeably different. While the modern-day brain organoids were smooth and spherical, the Neanderthal organoids were smaller and bumpier, with a popcorn shape. The findings suggest the gene played a major role in the development of the modern human brain.

There were also differences in the way their cells multiplied and how their synapses formed. In the archaic version of the organoids, neuronal activity occurred at an earlier stage, suggesting that the Neanderthal neural network may have matured faster than that of modern humans. But the neurons in the Neanderthal organoids didn’t synchronize in the same way that those in the modern human organoids did.

The brain organoids are still far from actual brains. They lack blood vessels, which provide the brain with oxygen, as well as many cell types that exist in a real brain. And a study published last year in Nature found that brain organoids don’t replicate the intricate circuitry of the brain. In other words, they’re simplified models of the most complex organ. Since many human brain diseases are specific to particular cell types and circuits in the brain, this presents a challenge for using organoids to accurately model these disorders.

Muotri knows his brain organoids have limitations. “You cannot compare an organ or adult brain,” he says. “The organoid is just an indication of things that might change during development. It’s an extrapolation.”

H. Isaac Chen, MD, a neurosurgeon at the University of Pennsylvania who wasn’t involved in the new study, says there are probably more genes than just NOVA1 that make our brains distinct from those of ancient humans.

“Introducing specific gene variants into brain organoids is an interesting approach for understanding how they influence brain development,” Chen tells Future Human. “But it is not likely that a single gene variant is completely responsible for the differences in brain development between humans and extinct hominin species.”

Many psychiatric conditions are polygenic — that is, they involve several, even hundreds, of mutations in different genes.

Muotri’s team wants to look at the other 60 genes and what happens when each, or a combination of two or more, are altered in brain organoids.

As brain organoids get more advanced, Chen and others have raised ethical concerns about their use in research. Muotri’s lab has previously made brain organoids that emit humanlike brain waves, raising the possibility that they could someday develop consciousness. He has called for ethical guidelines around experiments that involve implanting human brain organoids into lab animals. While other groups have been testing brain organoids in mice, Muotri says his team has no plans to do so with their Neanderthal mini brains.

Chen isn’t worried that the Neanderthal organoids will become conscious anytime soon though. He says the possibility of growing a thinking Neanderthal brain in the lab is still far off.

Former staff writer at Medium, where I covered biotech, genetics, and Covid-19 for OneZero, Future Human, Elemental, and the Coronavirus Blog.

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