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Novel study used brain organoids genetically modified to mimic now-extinct Neanderthals

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Novel study used brain organoids genetically modified to mimic now-extinct Neanderthals

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.

Funding for this research came, in part, from the Neanderthal Brain Foundation, National Institutes of Health (grants U19MH1073671, K12GM068524, K01AA026911), Brain and Behavior Research Foundation (NARSAD Independent Investigator Grant), National Science foundation (grant 1754451), Gordon and Betty Moore Foundation (grant GBMF3804), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (Capes, Brazil), FAPESP (São Paulo Research Foundation, grant 2017/26439-0), CNPq (Brazil’s National Council for Scientific and Technological Development, grants 431000/2016-6, 312047/2017-7) and Loulou Foundation.

Disclosure: Alysson R. Muotri is a co-founder and has equity interest in TISMOO, a company dedicated to genetic analysis and brain organoid modeling focusing on therapeutic applications customized for autism spectrum disorder and other neurological disorders with genetic origins. The terms of this arrangement have been reviewed and approved by the University of California San Diego in accordance with its conflict of interest policies.

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New snake discovery rewrites history, points to North America’s role in snake evolution

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Novel study used brain organoids genetically modified to mimic now-extinct Neanderthals


A new species of fossil snake unearthed in Wyoming is rewriting our understanding of snake evolution. The discovery, based on four remarkably well-preserved specimens found curled together in a burrow, reveals a new species named Hibernophis breithaupti. This snake lived in North America 34 million years ago and sheds light on the origin and diversification of boas and pythons.

Hibernophis breithaupti has unique anatomical features, in part because the specimens are articulated — meaning they were found all in one piece with the bones still arranged in the proper order — which is unusual for fossil snakes. Researchers believe it may be an early member of Booidea, a group that includes modern boas and pythons. Modern boas are widespread in the Americas, but their early evolution is not well understood.These new and very complete fossils add important new information, in particular, on the evolution of small, burrowing boas known as rubber boas.

Traditionally, there has been much debate on the evolution of small burrowing boas. Hibernophis breithaupti shows that northern and more central parts of North America might have been a key hub for their development. The discovery of these snakes curled together also hints at the oldest potential evidence for a behavior familiar to us today — hibernation in groups.

“Modern garter snakes are famous for gathering by the thousands to hibernate together in dens and burrows,” says Michael Caldwell, a U of A paleontologist who co-led the research along with his former graduate student Jasmine Croghan, and collaborators from Australia and Brazil. “They do this to conserve heat through the effect created by the ball of hibernating animals. It’s fascinating to see possible evidence of such social behavior or hibernation dating back 34 million years.”



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Good timing: Study unravels how our brains track time

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Ever hear the old adage that time flies when you’re having fun? A new study by a team of UNLV researchers suggests that there’s a lot of truth to the trope.

Many people think of their brains as being intrinsically synced to the human-made clocks on their electronic devices, counting time in very specific, minute-by-minute increments. But the study, published this month in the latest issue of the peer-reviewed Cell Press journal Current Biology, showed that our brains don’t work that way.

By analyzing changes in brain activity patterns, the research team found that we perceive the passage of time based on the number of experiences we have — not some kind of internal clock. What’s more, increasing speed or output during an activity appears to affect how our brains perceive time.

“We tell time in our own experience by things we do, things that happen to us,” said James Hyman, a UNLV associate professor of psychology and the study’s senior author. “When we’re still and we’re bored, time goes very slowly because we’re not doing anything or nothing is happening. On the contrary, when a lot of events happen, each one of those activities is advancing our brains forward. And if this is how our brains objectively tell time, then the more that we do and the more that happens to us, the faster time goes.”

Methodology and Findings

The findings are based on analysis of activity in the anterior cingulate cortex (ACC), a portion of the brain important for monitoring activity and tracking experiences. To do this, rodents were tasked with using their noses to respond to a prompt 200 times.

Scientists already knew that brain patterns are similar, but slightly different, each time you do a repetitive motion, so they set out to answer: Is it possible to detect whether these slight differences in brain pattern changes correspond with doing the first versus 200th motion in series? And does the amount of time it takes to complete a series of motions impact brain wave activity?

By comparing pattern changes throughout the course of the task, researchers observed that there are indeed detectable changes in brain activity that occur as one moves from the beginning to middle to end of carrying out a task. And regardless of how slowly or quickly the animals moved, the brain patterns followed the same path. The patterns were consistent when researchers applied a machine learning-based mathematical model to predict the flow of brain activity, bolstering evidence that it’s experiences — not time, or a prescribed number of minutes, as you would measure it on a clock — that produce changes in our neurons’ activity patterns.

Hyman drove home the crux of the findings by sharing an anecdote of two factory workers tasked with making 100 widgets during their shift, with one worker completing the task in 30 minutes and the other in 90 minutes.

“The length of time it took to complete the task didn’t impact the brain patterns. The brain is not a clock; it acts like a counter,” Hyman explained. “Our brains register a vibe, a feeling about time. …And what that means for our workers making widgets is that you can tell the difference between making widget No. 85 and widget No. 60, but not necessarily between No. 85 and No. 88.”

But exactly “how” does the brain count? Researchers discovered that as the brain progresses through a task involving a series of motions, various small groups of firing cells begin to collaborate — essentially passing off the task to a different group of neurons every few repetitions, similar to runners passing the baton in a relay race.

“So, the cells are working together and over time randomly align to get the job done: one cell will take a few tasks and then another takes a few tasks,” Hyman said. “The cells are tracking motions and, thus, chunks of activities and time over the course of the task.”

And the study’s findings about our brains’ perception of time applies to activities-based actions other than physical motions too.

“This is the part of the brain we use for tracking something like a conversation through dinner,” Hyman said. “Think of the flow of conversation and you can recall things earlier and later in the dinner. But to pick apart one sentence from the next in your memory, it’s impossible. But you know you talked about one topic at the start, another topic during dessert, and another at the end.”

By observing the rodents who worked quickly, scientists also concluded that keeping up a good pace helps influence time perception: “The more we do, the faster time moves. They say that time flies when you’re having fun. As opposed to having fun, maybe it should be ‘time flies when you’re doing a lot’.”

Takeaways

While there’s already a wealth of information on brain processes over very short time scales of less than a second, Hyman said that the UNLV study is groundbreaking in its examination of brain patterns and perception of time over a span of just a few minutes to hours — “which is how we live much of our life: one hour at a time. ”

“This is among the first studies looking at behavioral time scales in this particular part of the brain called the ACC, which we know is so important for our behavior and our emotions,” Hyman said.

The ACC is implicated in most psychiatric and neurodegenerative disorders, and is a concentration area for mood disorders, PTSD, addiction, and anxiety. ACC function is also central to various dementias including Alzheimer’s disease, which is characterized by distortions in time. The ACC has long been linked to helping humans with sequencing events or tasks such as following recipes, and the research team speculates that their findings about time perception might fall within this realm.

While the findings are a breakthrough, more research is needed. Still, Hyman said, the preliminary findings posit some potentially helpful tidbits about time perception and its likely connection to memory processes for everyday citizens’ daily lives. For example, researchers speculate that it could lend insights for navigating things like school assignments or even breakups.

“If we want to remember something, we may want to slow down by studying in short bouts and take time before engaging in the next activity. Give yourself quiet times to not move,” Hyman said. “Conversely, if you want to move on from something quickly, get involved in an activity right away.”

Hyman said there’s also a huge relationship between the ACC, emotion, and cognition. Thinking of the brain as a physical entity that one can take ownership over might help us control our subjective experiences.

“When things move faster, we tend to think it’s more fun — or sometimes overwhelming. But we don’t need to think of it as being a purely psychological experience, as fun or overwhelming; rather, if you view it as a physical process, it can be helpful,” he said. “If it’s overwhelming, slow down or if you’re bored, add activities. People already do this, but it’s empowering to know it’s a way to work your own mental health, since our brains are working like this already.”



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Another intermediate-mass black hole discovered at the center of our galaxy

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Novel study used brain organoids genetically modified to mimic now-extinct Neanderthals


While researching a cluster of stars in the immediate vicinity of the supermassive black hole SgrA* (Sagittarius A*) at the centre of our galaxy, an international team of researchers led by PD Dr Florian Peißker has found signs of another, intermediate-mass black hole. Despite enormous research efforts, only about ten of these intermediate-mass black holes have been found in our entire universe so far. Scientists believe that they formed shortly after the Big Bang. By merging, they act as ‘seeds’ for supermassive black holes. The study ‘The Evaporating Massive Embedded Stellar Cluster IRS 13 Close to Sgr A*. II. Kinematic structure’ was published in The Astrophysical Journal.

The analysed star cluster IRS 13 is located 0.1 light years from the centre of our galaxy. This is very close in astronomical terms, but would still require travelling from one end of our solar system to the other twenty times to cover the distance. The researchers noticed that the stars in IRS 13 move in an unexpectedly orderly pattern. They had actually expected the stars to be arranged randomly. Two conclusions can be drawn from this regular pattern: On the one hand, IRS 13 appears to interact with SgrA*, which leads to the orderly motion of the stars. On the other hand, there must be something inside the cluster for it to be able to maintain its observed compact shape.

Multi-wavelength observations with the Very Large Telescope as well as the ALMA and Chandra telescopes now suggest that the reason for the compact shape of IRS 13 could be an intermediate-mass black hole located at the centre of the star cluster. This would be supported by the fact that the researchers were able to observe characteristic X-rays and ionized gas rotating at a speed of several 100 km/s in a ring around the suspected location of the intermediate-mass black hole.

Another indication of the presence of an intermediate-mass black hole is the unusually high density of the star cluster, which is higher than that of any other known density of a star cluster in our Milky Way. “IRS 13 appears to be an essential building block for the growth of our central black hole SgrA*,” said Florian Peißker, first author of the study. “This fascinating star cluster has continued to surprise the scientific community ever since it was discovered around twenty years ago. At first it was thought to be an unusually heavy star. With the high-resolution data, however, we can now confirm the building-block composition with an intermediate-mass black hole at the centre.” Planned observations with the James Webb Space Telescope and the Extremely Large Telescope, which is currently under construction, will provide further insights into the processes within the star cluster.



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