He isolated DNA from Egyptian mummies. He discovered the Denisovans, an extinct species of ancient man, by sequencing DNA from a tiny piece of bone. He led a large study to reconstruct the Neanderthal genome - and found traces of their genes that still lurk in some of us today. Now Swedish geneticist Dr. Svante Paabo wants to turn paleontology upside down again - this time he plans to grow Neanderthal stem cells in tiny brain organoids in a test tube.
He does not plan to completely restore the Neanderthal brain in a vat - rather, he wants to use gene editing to give human stem cells several variants of genes found in Neanderthals. These edited stem cells are then placed into small brain cells that mimic fetal brain development, complete with their own blood vessels, neural networks, and functioning synapses.
By comparing the growth of nonandertalized mini-brains to that of a human, Paabo hopes to highlight the genetic factors that make us so special.
“The Neanderthals were intelligent like other mammals. They didn't go out into the ocean unless they saw the other shore,”says Paabo. “But for me the biggest question in the history of mankind is: why have we become so desperate?”
DNA revolution
Paleontologists have long wondered how evolution has blinded our amazing brains. By comparing our genetics to that of our closest ape cousins, geneticists have painstakingly isolated a handful of critically different genes. For example, small mutations in FOXP2 seem to underlie our ability to form complex phonemes and words. Some even believe that FOXP2 is a key biological benefit that our rich, rich language gives us.
Unfortunately, comparing genomes can only reveal genes that differ between humans and apes - but how these genes shaped our brain development remains unanswered.
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“In the past, we just limited ourselves to looking at sequencing data and cataloging differences in other primates,” laments neurogeneticist Simon Fischer, who runs the Max Planck Institute for Psycholinguistics in Nijmegen, the Netherlands. "We got a little disappointed after working with traditional instruments for so many years."
Now, thanks to amazing DNA technology, everything is about to change.
About thirty years ago, Paabo began to seriously consider a radical idea: can DNA be extracted from dead tissue? Although DNA is relatively stable compared to other biomolecules such as proteins, it begins to decay rapidly after death. The famous double helix, carefully coiled by nature into compact structures, breaks into shorter and shorter fragments over time. Putting these fragments back into coherent structures is proving to be extremely difficult, but in 1985, using the remains of a 2,400-year-old mummy, Paabo convincingly showed that this could be done.
This discovery threw open the doors of paleontology. Scientists are no longer bound by the traditional DNA of modern, living species; they now have a powerful tool to go back in time and explore the DNA lost in history.
Blinded by this initial success, Paabo turned to the Neanderthals, a mysterious branch of humans that went extinct more than 30,000 years ago. In 2016, he published the first complete Neanderthal genome, shocking scientists and the public with an intriguing result: 1 to 6 percent of Neanderthal genes were present in people from Europe, the Middle East and the Far East. In other words, at some point in ancient history, our ancestors danced horizontal tango with their Neanderthal cousins, and we are a direct legacy of these dances.
“Neanderthals have left a mark on the DNA of people living today. It is very cool. The Neanderthals were not completely extinct,”Paabo said at the time.
His discovery led to a broader question: To what extent are Neanderthals related to us? Like modern humans, these broad-jawed hominids with a prominent browbone lived in caves and painted on walls, created hats, and decorated their bodies with flowers long before modern humans set foot in Europe. However, they became extinct, and people reached a billion in number and scattered around the globe.
By comparing our genomes, Paabo's team identified several regions containing DNA variations - changes that could help humans adapt. Among them are genomic regions that play a role in cognitive development.
While our wildly different fates may not be entirely related to differences in cognition, Paabo thinks this is a good place to start. And thanks to the organelles of the brain, he can now test his idea.
Brain balls
Brain organoids are called differently: cerebral spheres, mini-brains, cerebral organelles. First invented in 2013, these bizarre balls or brain drops look quite creepy. But because their growth reflects the development of the human embryonic brain, these balls quickly became a favorite toy for neuroscientists.
There are many different recipes for making brain organelles, but they are usually made from human stem cells. Under close supervision, cells slowly develop into deformed pieces of brain tissue using a chemical soup. Like the real human brain, most drops contain a structure similar to the cerebral cortex, the wrinkled outer layer of the brain that organizes higher-level cognitive functions such as attention, language, and thought.
After a sufficient amount of time, neurons within the cerebral balls are filled with electrical activity and connect to neural networks, with some connections stretching through the entire organoid. These brain drops are not “mini-brains” in the sense that they can think or feel, no. But a careful analysis of their cellular composition and gene expression revealed a set of functional neuronal types, the combined work of which resembles the brain of a second trimester embryo.
In other words, brain balls are ideal candidates for studying brain development. Since their inception, they have been used to mimic autism, schizophrenia, and study the effects of the Zika virus on the fetal brain.
And now, thanks to Paabo, they will find applications in paleontology.
Revival of the Neanderthals
To restore the entire Neanderthal genome, scientists would have to change a million genes. This ambitious goal is currently not possible even with sophisticated genome editing tools like CRISPR.
Rather than roughly editing all of the Neanderthal variants into human stem cells, Paabo takes a more subtle approach: he introduces only three key genes that differ between humans and Neanderthals, and then tracks the effects of those genes on brain development.
This is a proven method.
Several years ago, working with Wieland Hattner, a neuroscientist at the Max Planck Institute for Molecular Cell Biology and Genetics, the team grew brain organelles using leukocytes from humans and other primates. The brain drops have evolved over several weeks, allowing scientists to compare and contrast how cell growth differs between species. Using live microscopy, scientists have found that human cells become one and a half times longer than monkeys in order to align their chromosomes before dividing into daughter cells. And this lengthening somehow helps humans generate far more neural stem cells than our closest primate relatives.
Paabo hopes to find more of these striking differences in Neanderthal mini-brains, as they might explain why modern humans have conquered as a species.
"The best result would be that the genetic changes lead to longer or more branched neuronal growth," he says. "You could say that this is the biological basis for why our brains function differently."
After all, this is only the beginning of the study of human uniqueness, which has become possible only now.
Ilya Khel