Novel study used brain organoids genetically modified to mimic now-extinct Neanderthals
Source: University of California, San
Diego
February 11, 2021 -- Researchers
discovered a single gene alteration that may help explain cognitive differences
between modern humans and our predecessor, and used that information to develop
Neanderthal-like brain organoids in the lab.
As a professor of pediatrics and
cellular and molecular medicine at University of California San Diego School of
Medicine, Alysson R. Muotri, PhD, has long studied how the brain develops and
what goes wrong in neurological disorders. For almost as long, he has also been
curious about the evolution of the human brain -- what changed that makes us so
different from preceding Neanderthals and Denisovans, our closest evolutionary
relatives, now extinct?
Evolutionary studies rely heavily on two
tools -- genetics and fossil analysis -- to explore how a species changes over
time. But neither approach can reveal much about brain development and function
because brains do not fossilize, Muotri said. There is no physical record to
study.
So Muotri decided to try stem cells, a
tool not often applied in evolutionary reconstructions. Stem cells, the
self-renewing precursors of other cell types, can be used to build brain
organoids -- "mini brains" in a laboratory dish. Muotri and
colleagues have pioneered the use of stem cells to compare humans to other
primates, such as chimpanzees and bonobos, but until now a comparison with
extinct species was not thought possible.
In a study published February 11, 2021
in Science, Muotri's team catalogued the differences between the
genomes of diverse modern human populations and the Neanderthals and
Denisovans, who lived during the Pleistocene Epoch, approximately 2.6 million
to 11,700 years ago. Mimicking an alteration they found in one gene, the
researchers used stem cells to engineer "Neanderthal-ized" brain
organoids.
"It's fascinating to see that a
single base-pair alteration in human DNA can change how the brain is
wired," said Muotri, senior author of the study and director of the UC San
Diego Stem Cell Program and a member of the Sanford Consortium for Regenerative
Medicine. "We don't know exactly how and when in our evolutionary history
that change occurred. But it seems to be significant, and could help explain
some of our modern capabilities in social behavior, language, adaptation,
creativity and use of technology."
The team initially found 61 genes that
differed between modern humans and our extinct relatives. One of these altered
genes -- NOVA1 -- caught Muotri's attention because it's a
master gene regulator, influencing many other genes during early brain
development. The researchers used CRISPR gene editing to engineer modern human
stem cells with the Neanderthal-like mutation in NOVA1. Then they
coaxed the stem cells into forming brain cells and ultimately Neanderthal-ized
brain organoids.
Brain organoids are little clusters of
brain cells formed by stem cells, but they aren't exactly brains (for one, they
lack connections to other organ systems, such as blood vessels). Yet organoids
are useful models for studying genetics, disease development and responses to
infections and therapeutic drugs. Muotri's team has even optimized the brain
organoid-building process to achieve organized electrical oscillatory waves
similar to those produced by the human brain.
The Neanderthal-ized brain organoids
looked very different than modern human brain organoids, even to the naked eye.
They had a distinctly different shape. Peering deeper, the team found that
modern and Neanderthal-ized brain organoids also differ in the way their cells
proliferate and how their synapses -- the connections between neurons -- form.
Even the proteins involved in synapses differed. And electrical impulses
displayed higher activity at earlier stages, but didn't synchronize in networks
in Neanderthal-ized brain organoids.
According to Muotri, the neural network
changes in Neanderthal-ized brain organoids parallel the way newborn non-human
primates acquire new abilities more rapidly than human newborns.
"This study focused on only one
gene that differed between modern humans and our extinct relatives. Next we
want to take a look at the other 60 genes, and what happens when each, or a
combination of two or more, are altered," Muotri said.
"We're looking forward to this new
combination of stem cell biology, neuroscience and paleogenomics. The ability
to apply the comparative approach of modern humans to other extinct hominins,
such as Neanderthals and Denisovans, using brain organoids carrying ancestral
genetic variants is an entirely new field of study."
To continue this work, Muotri has teamed
up with Katerina Semendeferi, professor of anthropology at UC San Diego and
study co-author, to co-direct the new UC San Diego Archealization Center, or
ArchC.
"We will merge and integrate this
amazing stem cell work with anatomic comparisons from several species and
neurological conditions to create downstream hypotheses about brain function of
our extinct relatives," Semendeferi said. "This neuro-archealization
approach will complement efforts to understand the mind of our ancestors and
close relatives, like the Neanderthals."
Co-authors of the study include: Cleber
A. Trujillo, Isaac A. Chaim, Emily C. Wheeler, Assael A. Madrigal, Justin
Buchanan, Sebastian Preissl, Allen Wang, Priscilla D. Negraes, and Ryan Szeto,
UC San Diego; Edward S. Rice, Nathan K. Schaefer, Ashley Byrne, Maximillian
Marin, Christopher Vollmers, Angela N. Brooks, Richard E. Green, UC Santa Cruz;
Roberto H. Herai, Pontifícia Universidade Católica do Paraná; Alik Huseynov,
Imperial College London; Mariana S.A. Ferraz, Fernando da S. Borges, Alexandre
H. Kihara, Universidade Federal do ABC; Jonathan D. Lautz, Stephen E.P. Smith,
Seattle Children's Research Institute and University of Washington; Beth
Shapiro, UC Santa Cruz and Howard Hughes Medical Institute; and Gene W. Yeo, UC
San Diego, Agency for Science, Technology and Research (Singapore) and National
University of Singapore.
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