TOP SCEINCE
Brain ‘assembloids’ mimic human blood-brain barrier
In a pioneering achievement, a research team led by experts at Cincinnati Children’s have developed the world’s first human mini-brain that incorporates a fully functional blood-brain barrier (BBB).
“Lack of an authentic human BBB model has been a major hurdle in studying neurological diseases,” says lead corresponding author Ziyuan Guo, PhD, “Our breakthrough involves the generation of human BBB organoids from human pluripotent stem cells, mimicking human neurovascular development to produce a faithful representation of the barrier in growing, functioning brain tissue. This is an important advance because animal models we currently use in research do not accurately reflect human brain development and BBB functionality.”
What is the blood-brain barrier?
Unlike the rest of our bodies, blood vessels in the brain feature an extra lining of tightly packed cells that sharply limit the size of molecules that can pass from the bloodstream into the central nervous system (CNS).
A properly functioning barrier maintains brain health by preventing the entry of harmful substances while allowing essential nutrients to reach the brain. However, that same barrier also prevents many potentially helpful medicines from reaching the brain. Also, several neurological disorders are caused, or worsened, when the blood-brain barrier forms improperly or begins breaking down.
Significant differences between human and animal brains have resulted in many hopeful new drugs that were developed relying heavily on animal models to fail later when tested in human study participants.
“Now, through stem cell bioengineering, we have developed an innovative platform based on human stem cells that allows us to study the intricate mechanisms governing BBB function and dysfunction. This provides unprecedented opportunities for drug discovery and therapeutic intervention,” Guo says.
Overcoming a long-running challenge
Research teams worldwide have been racing to develop brain organoids — tiny, growing 3D structures that mimic the early steps of brain formation. Unlike cell types grown flat in a lab dish, organoid cells are connected. They self-assemble into spherical forms. Their cells “talk” to each other like human cells normally do during fetal development.
Cincinnati Children’s has been a leader in developing other types of organoids, including the world’s first functional intestine, stomach and esophagus organoids. But until now, no research center had succeeded at making a brain organoid that features the special barrier lining found in human brain blood vessels.
The research team calls their new model “BBB assembloids.” Their name reflects the advance that made the breakthrough possible. These assembloids combine two distinct types of organoids: brain organoids that replicate human brain tissue and blood vessel organoids that mimic vascular structures.
The combination process began with brain organoids measuring 3 to 4 millimeters in diameter and blood vessel organoids about 1 millimeter in diameter. Over the course of about a month, these separate structures fused into a single sphere measuring slightly more than 4 millimeters in diameter (about 1/8 of an inch, or roughly the size of a sesame seed).
These integrated organoids recreate many of the complex neurovascular interactions observed in the human brain, but they are not complete models of the brain. For example, the tissue does not contain immune cells and there are no connections to the rest of the body’s nervous system.
Research teams at Cincinnati Children’s have shown other successes at merging and layering organoids from different cell types to form more complex “next generation” organoids. Those successes helped inform the new brain organoid work.
Importantly, the BBB assembloids can be grown using neurotypical human stem cells or stem cells from people with specific brain diseases, thus reflecting gene variants and other conditions that can lead to a malfunctioning blood-brain barrier.
Initial proof of concept
To demonstrate the potential utility of the new assembloids, the researcher team used a line of patient-derived stem cells to make assembloids that accurately replicated key features of a rare brain condition called a cerebral cavernous malformation.
This genetic disorder, which is characterized by dysfunctional blood-brain barrier integrity, results in clusters of abnormal blood vessels in the brain that often resemble raspberries in their appearance. The disorder significantly increases risk of stroke.
“Our model accurately recapitulated the disease phenotype, offering new insights into the underlying molecular and cellular pathology of cerebral vascular disorders,” Guo says.
Potential applications
The co-authors envision a variety of potential uses of BBB assembloids:
- Personalized Drug Screening: Patient-derived BBB assembloids could serve as avatars to tailor therapies for patients based on their unique genetic and molecular profiles.
- Disease Modeling: A number of neurovascular disorders, including rare and genetically complex conditions, lack good model systems for research. Success at making BBB assembloids could accelerate development of human brain tissue models for more conditions.
- High-Throughput Drug Discovery: Scaling up assembloid production could allow more accurate, and more rapid analysis of whether potential brain medications can effectively cross the BBB.
- Environmental Toxin Testing: Often based heavily on animal model systems, BBB assembloids could help evaluate the toxic effects of environmental pollutants, pharmaceuticals, and other chemical compounds.
- Immunotherapy Development: Through investigating the role of the BBB in neuroinflammatory and neurodegenerative diseases, the new assembloids could support delivering immune-based therapies to the brain.
- Bioengineering and Biomaterials Research: Biomedical engineers and materials scientists will likely benefit from having a lab model of the BBB to test novel biomaterials, drug delivery vehicles, and tissue engineering strategies.
“Overall, BBB assembloids represent a game-changing technology with broad implications for neuroscience, drug discovery, and personalized medicine,” Guo says.
About the study
In addition to Guo, the co-first authors of the study were: Lan Dao, MS, and Lu Lu, PhD, from Cincinnati Children’s; Tianyang Xu from UC San Diego; and Zhen You from the Mayo Clinic. Co-corresponding authors were Sheng Zhong, PhD, from UC San Diego and L. Frank Huang, PhD, from the Mayo Clinic.
Co-authors from Cincinnati Children’s also included Avijite Kumer Sarkar, PhD, Hui Zhu, PhD, George Yoshida, BA, Yifei Miao, PhD, Sarah Mierke, MD, Srijan Kalva, Mingxia Gu, MD, PhD, and Sudhakar Vadivelu, MD. The Single Cell Genomics Facility at Cincinnati Children’s and the NIH NeuroBioBank also provided key support to the research.
Guo and Dao have a pending patent application (“Vascularized brain organoids having a CCM-like feature and methods of making and use,” U.S. Application no. 63/510,463) related to this research. Zhong is a founder of Genemo, Inc.
TOP SCEINCE
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.
TOP SCEINCE
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.
TOP SCEINCE
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.
-
Solar Energy3 years ago
DLR testing the use of molten salt in a solar power plant in Portugal
-
world news1 year ago
Gulf, France aid Gaza, Russia evacuates citizens
-
Camera1 year ago
DJI Air 3 vs. Mini 4 Pro: which compact drone is best?
-
world news1 year ago
Strong majority of Americans support Israel-Hamas hostage deal
-
Camera4 years ago
Charles ‘Chuck’ Geschke, co-founder of Adobe and inventor of the PDF, dies at 81
-
Solar Energy1 year ago
Glencore eyes options on battery recycling project
-
Camera1 year ago
Sony a9 III: what you need to know
-
Indian Defense3 years ago
Israeli Radar Company Signs MoU To Cooperate With India’s Alpha Design Technologies