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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?
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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Early dark energy could resolve cosmology’s two biggest puzzles
A new study by MIT physicists proposes that a mysterious force known as early dark energy could solve two of the biggest puzzles in cosmology and fill in some major gaps in our understanding of how the early universe evolved.
Now, the MIT team has found that both puzzles could be resolved if the early universe had one extra, fleeting ingredient: early dark energy. Dark energy is an unknown form of energy that physicists suspect is driving the expansion of the universe today. Early dark energy is a similar, hypothetical phenomenon that may have made only a brief appearance, influencing the expansion of the universe in its first moments before disappearing entirely.
Some physicists have suspected that early dark energy could be the key to solving the Hubble tension, as the mysterious force could accelerate the early expansion of the universe by an amount that would resolve the measurement mismatch.
The MIT researchers have now found that early dark energy could also explain the baffling number of bright galaxies that astronomers have observed in the early universe. In their new study, reported in the Monthly Notices of the Royal Astronomical Society, the team modeled the formation of galaxies in the universe’s first few hundred million years. When they incorporated a dark energy component only in that earliest sliver of time, they found the number of galaxies that arose from the primordial environment bloomed to fit astronomers’ observations.
“You have these two looming open-ended puzzles,” says study co-author Rohan Naidu, a postdoc in MIT’s Kavli Institute for Astrophysics and Space Research. “We find that in fact, early dark energy is a very elegant and sparse solution to two of the most pressing problems in cosmology.”
The study’s co-authors include lead author and Kavli postdoc Xuejian (Jacob) Shen, and MIT professor of physics Mark Vogelsberger, along with Michael Boylan-Kolchin at the University of Texas at Austin, and Sandro Tacchella at the University of Cambridge.
Big city lights
Based on standard cosmological and galaxy formation models, the universe should have taken its time spinning up the first galaxies. It would have taken billions of years for primordial gas to coalesce into galaxies as large and bright as the Milky Way.
But in 2023, NASA’s James Webb Space Telescope (JWST) made a startling observation. With an ability to peer farther back in time than any observatory to date, the telescope uncovered a surprising number of bright galaxies as large as the modern Milky Way within the first 500 million years, when the universe was just 3 percent of its current age.
“The bright galaxies that JWST saw would be like seeing a clustering of lights around big cities, whereas theory predicts something like the light around more rural settings like Yellowstone National Park,” Shen says. “And we don’t expect that clustering of light so early on.”
For physicists, the observations imply that there is either something fundamentally wrong with the physics underlying the models or a missing ingredient in the early universe that scientists have not accounted for. The MIT team explored the possibility of the latter, and whether the missing ingredient might be early dark energy.
Physicists have proposed that early dark energy is a sort of antigravitational force that is turned on only at very early times. This force would counteract gravity’s inward pull and accelerate the early expansion of the universe, in a way that would resolve the mismatch in measurements. Early dark energy, therefore, is considered the most likely solution to the Hubble tension.
Galaxy skeleton
The MIT team explored whether early dark energy could also be the key to explaining the unexpected population of large, bright galaxies detected by JWST. In their new study, the physicists considered how early dark energy might affect the early structure of the universe that gave rise to the first galaxies. They focused on the formation of dark matter halos — regions of space where gravity happens to be stronger, and where matter begins to accumulate.
“We believe that dark matter halos are the invisible skeleton of the universe,” Shen explains. “Dark matter structures form first, and then galaxies form within these structures. So, we expect the number of bright galaxies should be proportional to the number of big dark matter halos.”
The team developed an empirical framework for early galaxy formation, which predicts the number, luminosity, and size of galaxies that should form in the early universe, given some measures of “cosmological parameters.” Cosmological parameters are the basic ingredients, or mathematical terms, that describe the evolution of the universe.
Physicists have determined that there are at least six main cosmological parameters, one of which is the Hubble constant — a term that describes the universe’s rate of expansion. Other parameters describe density fluctuations in the primordial soup, immediately after the Big Bang, from which dark matter halos eventually form.
The MIT team reasoned that if early dark energy affects the universe’s early expansion rate, in a way that resolves the Hubble tension, then it could affect the balance of the other cosmological parameters, in a way that might increase the number of bright galaxies that appear at early times. To test their theory, they incorporated a model of early dark energy (the same one that happens to resolve the Hubble tension) into an empirical galaxy formation framework to see how the earliest dark matter structures evolve and give rise to the first galaxies.
“What we show is, the skeletal structure of the early universe is altered in a subtle way where the amplitude of fluctuations goes up, and you get bigger halos, and brighter galaxies that are in place at earlier times, more so than in our more vanilla models,” Naidu says. “It means things were more abundant, and more clustered in the early universe.”
“A priori, I would not have expected the abundance of JWST’s early bright galaxies to have anything to do with early dark energy, but their observation that EDE pushes cosmological parameters in a direction that boosts the early-galaxy abundance is interesting,” says Marc Kamionkowski, professor of theoretical physics at Johns Hopkins University, who was not involved with the study. “I think more work will need to be done to establish a link between early galaxies and EDE, but regardless of how things turn out, it’s a clever — and hopefully ultimately fruitful — thing to try.”
“We demonstrated the potential of early dark energy as a unified solution to the two major issues faced by cosmology. This might be an evidence for its existence if the observational findings of JWST get further consolidated,” Vogelsberger concludes. “In the future, we can incorporate this into large cosmological simulations to see what detailed predictions we get.”
This research was supported, in part, by NASA and the National Science Foundation.
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Plant-derived secondary organic aerosols can act as mediators of plant-plant interactions
A new study published in Science reveals that plant-derived secondary organic aerosols (SOAs) can act as mediators of plant-plant interactions. This research was conducted through the cooperation of chemical ecologists, plant ecophysiologists and atmospheric physicists at the University of Eastern Finland.
The study showed that Scots pine seedlings, when damaged by large pine weevils, release VOCs that activate defences in nearby plants of the same species. Interestingly, the biological activity persisted after VOCs were oxidized to form SOAs. The results indicated that the elemental composition and quantity of SOAs likely determines their biological functions.
“A key novelty of the study is the finding that plants adopt subtly different defence strategies when receiving signals as VOCs or as SOAs, yet they exhibit similar degrees of resistance to herbivore feeding,” said Professor James Blande, head of the Environmental Ecology Research Group. This observation opens up the possibility that plants have sophisticated sensing systems that enable them to tailor their defences to information derived from different types of chemical cue.
“Considering the formation rate of SOAs from their precursor VOCs, their longer lifetime compared to VOCs, and the atmospheric air mass transport, we expect that the ecologically effective distance for interactions mediated by SOAs is longer than that for plant interactions mediated by VOCs,” said Professor Annele Virtanen, head of the Aerosol Physics Research Group. This could be interpreted as plants being able to detect cues representing close versus distant threats from herbivores.
The study is expected to open up a whole new complex research area to environmental ecologists and their collaborators, which could lead to new insights on the chemical cues structuring interactions between plants.
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Folded or cut, this lithium-sulfur battery keeps going
Most rechargeable batteries that power portable devices, such as toys, handheld vacuums and e-bikes, use lithium-ion technology. But these batteries can have short lifetimes and may catch fire when damaged. To address stability and safety issues, researchers reporting in ACS Energy Letters have designed a lithium-sulfur (Li-S) battery that features an improved iron sulfide cathode. One prototype remains highly stable over 300 charge-discharge cycles, and another provides power even after being folded or cut.
The team coated iron sulfide cathodes in different polymers and found in initial electrochemical performance tests that polyacrylic acid (PAA) performed best, retaining the electrode’s discharge capacity after 300 charge-discharge cycles. Next, the researchers incorporated a PAA-coated iron sulfide cathode into a prototype battery design, which also included a carbonate-based electrolyte, a lithium metal foil as an ion source, and a graphite-based anode. They produced and then tested both pouch cell and coin cell battery prototypes.
After more than 100 charge-discharge cycles, Wang and colleagues observed no substantial capacity decay in the pouch cell. Additional experiments showed that the pouch cell still worked after being folded and cut in half. The coin cell retained 72% of its capacity after 300 charge-discharge cycles. They next applied the polymer coating to cathodes made from other metals, creating lithium-molybdenum and lithium-vanadium batteries. These cells also had stable capacity over 300 charge-discharge cycles. Overall, the results indicate that coated cathodes could produce not only safer Li-S batteries with long lifespans, but also efficient batteries with other metal sulfides, according to Wang’s team.
The authors acknowledge funding from the National Natural Science Foundation of China; the Natural Science Foundation of Sichuan, China; and the Beijing National Laboratory for Condensed Matter Physics.
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