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Brain ‘assembloids’ mimic human blood-brain barrier

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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).

This major advance, published May 15, 2024, in Cell Stem Cell, promises to accelerate the understanding and improved treatment of a wide range of brain disorders, including stroke, cerebral vascular disorders, brain cancer, Alzheimer’s disease, Huntington disease, Parkinson’s disease, and other neurodegenerative conditions.

“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.



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Paleontology: New fossil fish genus discovered

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Paleontology: New fossil fish genus discovered


Gobies or Gobioidei are one of the most species-rich groups of marine and freshwater fish in Europe. Spending most of their lives on the bottom of shallow waterbodies, they make substantial contributions to the functioning of many ecosystems. With the identification of a new genus of a fossil freshwater goby, students of the international master program ‘Geobiology and Paleobiology’ at LMU and paleontologist Bettina Reichenbacher, professor at the Department of Earth and Environmental Sciences at LMU, have made a discovery that provides critical insights into the evolutionary history of these fish.

Measuring up to 34 mm, the small fish of the new genus †Simpsonigobius were discovered in 18-million-year-old rocks in Turkey and are marked by a distinct combination of morphological features, including otoliths (hearing stones) with a unique shape.

Modern research techniques elucidate position in family tree

To determine the relationships of †Simpsonigobius within the gobioid phylogenetic tree, the researchers utilized a “total-evidence” phylogenetic dataset, which they enhanced in order to combine a total of 48 morphological characters and genetic data from five genes for 48 living and 10 fossil species. In addition, the team employed “tip-dating” for fossil gobioid species for the first time. This is a phylogenetic method in which the age of the fossils (= tips) included in the phylogenetic tree is used to infer the timing of the evolutionary history of the entire group.

The results show that the new genus is the oldest skeleton-based member of the family Oxudercidae — which is classified among the “modern” gobies (families Gobiidae and Oxudercidae) — and the oldest freshwater goby within this modern group. The tip-dating analysis estimated the emergence of the Gobiidae at 34.1 million years ago and that of the Oxudercidae at 34.8 million years ago, which is consistent with previous dating studies using other methods. Moreover, stochastic habitat mapping, in which the researchers incorporated fossil gobies for the first time, revealed that the gobies probably possessed broad salinity tolerance at the beginning of their evolutionary history, which challenges previous assumptions.

“The discovery of †Simpsonigobius not only adds a new genus to the Gobioidei, but also provides vital clues about the evolutionary timeline and habitat adaptations of these diverse fishes. Our research highlights the importance of analyzing fossil records using modern methods to achieve a more accurate picture of evolutionary processes,” says Reichenbacher. First author Moritz Dirnberger, currently a doctoral candidate at the University of Montpellier, adds: “The findings are expected to pave the way for further studies on gobioid evolution and the role of environmental factors in shaping their diversity.”



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Ancient ocean slowdown warns of future climate chaos

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Ancient ocean slowdown warns of future climate chaos


When it comes to the ocean’s response to global warming, we’re not in entirely uncharted waters. A UC Riverside study shows that episodes of extreme heat in Earth’s past caused the exchange of waters from the surface to the deep ocean to decline.

This system has been described as the “global conveyer belt,” because it redistributes heat around the globe through the movement of the ocean waters, making large portions of the planet habitable.

Using tiny, fossilized shells recovered from ancient deep-sea sediments, the study in the Proceedings of the National Academy of Sciences demonstrates how the conveyor belt responded around 50 million years ago. At that time, Earth’s climate resembled conditions predicted by the end of this century, if significant action is not taken to reduce carbon emissions.

Oceans play a crucial role in regulating Earth’s climate. They move warm water from the equator toward the north and south poles, balancing the planet’s temperatures. Without this circulation system, the tropics would be much hotter and the poles much colder. Changes in this system are linked to significant and abrupt climate change.

Furthermore, the oceans serve a critical role in removing anthropogenic carbon dioxide from the atmosphere. “The oceans are by far the largest standing pool of carbon on Earth’s surface today,” said Sandra Kirtland Turner, vice-chair of UCR’s Department of Earth and Planetary Sciences and first author of the study.

“Today, the oceans contain nearly 40,000 billion tons of carbon — more than 40 times the amount of carbon in the atmosphere. Oceans also take up about a quarter of anthropogenic CO2 emissions,” Kirtland Turner said. “If ocean circulation slows, absorption of carbon into the ocean may also slow, amplifying the amount of CO2 that stays in the atmosphere.”

Previous studies have measured changes in ocean circulation in Earth’s more recent geologic past, such as coming out of the last ice age; however, those do not approximate the levels of atmospheric CO2 or warming happening to the planet today. Other studies provide the first evidence that deep ocean circulation, particularly in the North Atlantic, is already starting to slow.

To better predict how ocean circulation responds to greenhouse gas-driven global warming, the research team looked to the early Eocene epoch, between roughly 49 and 53 million years ago. Earth then was much warmer than today, and that high-heat baseline was punctuated by spikes in CO2 and temperature called hyperthermals.

During that period, the deep ocean was up to 12 degrees Celsius warmer than it is today. During the hyperthermals, the oceans warmed an additional 3 degrees Celsius.

“Though the exact cause of the hyperthermal events is debated, and they occurred long before the existence of humans, these hyperthermals are the best analogs we have for future climate change,” Kirtland Turner said.

By analyzing tiny fossil shells from different sea floor locations around the globe, the researchers reconstructed patterns of deep ocean circulation during these hyperthermal events. The shells are from microorganisms called foraminifera, which can be found living throughout the world’s oceans, both on the surface and on the sea floor. They are about the size of a period at the end of a sentence.

“As the creatures are building their shells, they incorporate elements from the oceans, and we can measure the differences in the chemistry of these shells to broadly reconstruct information about ancient ocean temperatures and circulation patterns,” Kirtland Turner said.

The shells themselves are made of calcium carbonate. Oxygen isotopes in the calcium carbonate are indicators of temperatures in the water the organisms grew in, and the amount of ice on the planet at the time.

The researchers also examined carbon isotopes in the shells, which reflect the age of the water where the shells were collected, or how long water has been isolated from the ocean surface. In this way, they can reconstruct patterns of deep ocean water movement.

Foraminifera can’t photosynthesize, but their shells indicate the impact of photosynthesis of other organisms nearby, like phytoplankton. “Photosynthesis occurs in the surface ocean only, so water that has recently been at the surface has a carbon-13 rich signal that is reflected in the shells when that water sinks to the deep ocean,” Kirtland Turner said.

“Conversely, water that has been isolated from the surface for a long time has built up relatively more carbon-12 as the remains of photosynthetic organisms sink and decay. So, older water has relatively more carbon-12 compared to ‘young’ water.”

Scientists often make predictions about ocean circulation today using computer climate models. They use these models to answer the question: ‘how is the ocean going to change as the planet keeps warming?’ This team similarly used models to simulate the ancient ocean’s response to warming. They then used the foraminifera shell analysis to help test results from their climate models.

During the Eocene, there were about 1,000 parts per million (ppm) of carbon dioxide in the atmosphere, which contributed to that era’s high temperatures. Today, the atmosphere holds about 425 ppm.

However, humans emit nearly 37 billion tons of CO2 into the atmosphere each year; if these emission levels continue, similar conditions to the Early Eocene could occur by the end of this century.

Therefore, Kirtland Turner argues it is imperative to make every effort to reduce emissions.

“It’s not an all-or-nothing situation,” she said. “Every incremental bit of change is important when it comes to carbon emissions. Even small reductions of CO2 correlate to less impacts, less loss of life, and less change to the natural world.”



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Pacific coast gray whales have gotten 13% shorter in the past 20-30 years, Oregon State study finds

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Pacific coast gray whales have gotten 13% shorter in the past 20-30 years, Oregon State study finds


Gray whales that spend their summers feeding in the shallow waters off the Pacific Northwest coast have undergone a significant decline in body length since around the year 2000, a new Oregon State University study found.

The smaller size could have major consequences for the health and reproductive success of the affected whales, and also raises alarm bells about the state of the food web in which they coexist, researchers say.

“This could be an early warning sign that the abundance of this population is starting to decline, or is not healthy,” said K.C. Bierlich, co-author on the study and an assistant professor at OSU’s Marine Mammal Institute in Newport. “And whales are considered ecosystem sentinels, so if the whale population isn’t doing well, that might say a lot about the environment itself.”

The study, published in Global Change Biology, looked at the Pacific Coast Feeding Group (PCFG), a small subset of about 200 gray whales within the larger Eastern North Pacific (ENP) population of around 14,500. This subgroup stays closer to shore along the Oregon coast, feeding in shallower, warmer waters than the Arctic seas where the bulk of the gray whale population spends most of the year.

Recent studies from OSU have shown that whales in this subgroup are smaller and in overall worse body condition than their ENP counterparts. The current study reveals that they’ve been getting smaller in recent decades.

The Marine Mammal Institute’s Geospatial Ecology of Marine Megafauna (GEMM) Lab has been studying this subgroup of gray whales since 2016, including flying drones over the whales to measure their size. Using images from 2016-2022 of 130 individual whales with known or estimated age, researchers determined that a full-grown gray whale born in 2020 is expected to reach an adult body length that is 1.65 meters (about 5 feet, 5 inches) shorter than a gray whale born prior to 2000. For PCFG gray whales that grow to be 38-41 feet long at full maturity, that accounts for a loss of more than 13% of their total length.

If the same trend were to happen in humans, that would be like the height of the average American woman shrinking from 5 feet, 4 inches to 4 feet, 8 inches tall over the course of 20 years.

“In general, size is critical for animals,” said Enrico Pirotta, lead author on the study and a researcher at the University of St. Andrews in Scotland. “It affects their behavior, their physiology, their life history, and it has cascading effects for the animals and for the community they’re a part of.”

Whale calves that are smaller at weaning age may be unable to cope with the uncertainty that comes with being newly independent, which can affect survival rates, Pirotta said.

For adult gray whales, one of the biggest concerns is reproductive success.

“With them being smaller, there are questions of how effectively these PCFG gray whales can store and allocate energy toward growing and maintaining their health. Importantly, are they able to put enough energy toward reproduction and keep the population growing?” Bierlich said.

Scarring on PCFG whales from boat strikes and fishing gear entanglement also makes the team concerned that smaller body size with lower energy reserves may make the whales less resilient to injuries.

The study also examined the patterns of the ocean environment that likely regulate food availability for these gray whales off the Pacific coast by tracking cycles of “upwelling” and “relaxation” in the ocean. Upwelling sweeps nutrients from deeper to shallower regions, while relaxation periods then allow those nutrients to remain in shallower areas where light allows for growth of plankton and other tiny organisms, including the prey of gray whales.

“Without a balance between upwelling and relaxation, the ecosystem may not be able to produce enough prey to support the large size of these gray whales,” said co-author Leigh Torres, associate professor and director of the GEMM Lab at OSU.

The data show that whale size declined concurrently with changes in the balance between upwelling and relaxation, Pirotta said.

“We haven’t looked specifically at how climate change is affecting these patterns, but in general we know that climate change is affecting the oceanography of the Northeast Pacific through changes in wind patterns and water temperature,” he said. “And these factors and others affect the dynamics of upwelling and relaxation in the area.”

Now that they know the PCFG gray whales’ body size is declining, researchers say they have a lot of new questions about downstream consequences of that decline and the factors that could be contributing to it.

“We’re heading into our ninth field season studying this PCFG subgroup,” Bierlich said. “This is a powerful dataset that allows us to detect changes in body condition each year, so now we’re examining the environmental drivers of those changes.”

The other co-authors on the paper were Lisa Hildebrand, Clara Bird and Alejandro Ajó at OSU and Leslie New at Ursinus College in Pennsylvania.



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