Written by: Devin Juros ‘23
Edited by: Pradyut Sekhsaria ‘24
On the journey toward better understanding human cognition, research has focused on how humans today evolved to have the brain and mental faculties that separate us from other related species. Toward this goal, researchers are investigating differences in neurodevelopmental genes between current humans and our extinct evolutionary relatives, the Neanderthals and Denisovans. However, without being able to recreate these Neanderthal-esque genetic changes in living humans, it has been difficult to discern which genes are most important for our diverging cognitive abilities. But, perhaps now there is a way to get this information; not by mutating living humans but by mutating mini-brains grown in a dish. This cluster of cells functionally resembling the human brain could elicit a paradigm shift in our approach to understanding the evolution of various organs in different species.
Neanderthals and Denisovans were humanoid mammals who lived from approximately 200,000 to 50,000 years ago [3,5]. Though these early hominids had complex social interactions, tool development, and even possibly art, their cognitive abilities and neurodevelopment differed from current day humans [4,1]. But, since the brain quickly degrades, scientists have been left with only genetic material from the bones of early hominid remains to try to piece together how their brains developed differently than ours [6,2].
A better approach to this problem may have been developed by the Muotri Lab, which recently took a novel tact to assess the importance of neurodevelopment genes that differ between early hominids and current humans: brain organoids . To generate a brain organoid, which is essentially a mini-brain, human stem cells are put in a petri dish along with specific nutrients to support cell growth. These cells divide, become heterogenous, and form complex groupings that exhibit stability, self-renewal, and some functional aspects of a human brain.
Muotri et al., then used CRISPR-Cas9 to mutate these human brain organoids so that they had a mutation in the NOVA1 gene that mimicked the Neanderthal and Denisovan version of this gene. NOVA1 is an important gene for neurodevelopment and is expressed in a different form in current humans compared to early hominids. This led researchers to think that differences in this gene could have contributed to the differences in neurodevelopment and cognitive abilities between current humans and early hominids.
The researchers then compared human brain organoids to the brain organoids with the NOVA1 mutations, possibly recapitulating aspects of early hominid brains. They found that this NOVA1 mutation led to smaller brain organoids having a rougher morphology and disrupted synchrony of their neural activity. In addition, mutating NOVA1 led to changes in other genes involved in neurodevelopment and neural connectivity. All of these changes suggest that the form of NOVA1 that Neanderthals and Denisovans had could have been vital for differences in their neurodevelopment and cognition compared to current humans.
Though this research pushes forward our understanding of neurodevelopment and human brain evolution, it does come with some caveats. One primary limitation of this study is that other genes beside NOVA1 are different in current humans compared to early hominids. Therefore, the Neanderthal-esque mutation in NOVA1 in human brain cells could have led to different functional and structural changes than it would have had in a Neanderthal brain. Investigating more neurodevelopmental genes that differ in form between current humans and early hominids could help to parse out the complex differences in their brains.
This research also creates a novel path to investigate the evolution of other organs in humans and other species. Instead of just assessing differences in organ function and structure between species and then comparing this to genetic differences, evolutionary biologists can use CRISPR-Cas9 to see how specific genetic alterations lead to differences in the function and structure of other organoids. Organoids have already been developed for the brain, lung, colon, heart, and more, permitting a wide range of study into the evolution of different organs. Evolutionary biology will reap the benefits of the more direct nature of this new paradigm toward studying organ evolution across species.
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 Groeneveld, E. (2021, February 20). Denisovan. Retrieved February 22, 2021, from https://www.ancient.eu/Denisovan/
 Marris, E. (2018, February 22). Neanderthal artists made oldest-known cave paintings. Retrieved February 22, 2021, from https://www.nature.com/articles/d41586-018-02357-8
 Neanderthal. (n.d.). Retrieved February 22, 2021, from https://www.britannica.com/topic/Neanderthal
 The brains of Neanderthals and modern humans developed differently. (2010, November 08). Retrieved February 22, 2021, from https://www.mpg.de/623578/pressRelease201011021
 Trujillo, C. A., Rice, E. S., Schaefer, N. K., Chaim, I. A., Wheeler, E. C., Madrigal, A. A., . . . Muotri, A. R. (2021). Reintroduction of the archaic variant of nova1 in Cortical Organoids alters neurodevelopment. Science, 371(6530). doi:10.1126/science.aax2537
[Image Citation] Trujillo, C. A., Rice, E. S., Schaefer, N. K., Chaim, I. A., Wheeler, E. C., Madrigal, A. A., . . . Muotri, A. R. (2021). Reintroduction of the archaic variant of nova1 in Cortical Organoids alters neurodevelopment. Science, 371(6530). doi:10.1126/science.aax2537