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First multi-chamber heart organoids unravel human heart development and disease
Heart disease kills 18 million people each year, but the development of new therapies faces a bottleneck: no physiological model of the entire human heart exists — so far. A new multi-chamber organoid that mirrors the heart’s intricate structure enables scientists to advance screening platforms for drug development, toxicology studies, and understanding heart development. The new findings, using heart organoid models developed by Sasha Mendjan’s group at the Institute of Molecular Biotechnology (IMBA) of the Austrian Academy of Sciences, are presented in the journal Cell on November 28.
In 2021, the Mendjan lab presented the first chamber-like organoid heart model formed from human induced pluripotent stem cells. These self-organizing heart organoids, or Cardioids, recapitulated the development of the heart’s left ventricular chamber in the very early days of embryogenesis. “These Cardioids were a proof-of-principle and an important step forward,” says Mendjan. “While most adult diseases affect the left ventricle, which pumps oxygenated blood through the body, congenital defects affect mostly other heart regions essential to establish and maintain circulation.”
In the new study, the team at IMBA expanded on their previous work. The researchers first derived organoid models of each developing heart structure individually. “Then we asked: If we let all these organoids co-develop together, do we get a heart model that co-ordinately beats like the early human heart?,” Mendjan explains.
Unraveling human heart development
After growing left and right ventricular and the atrial organoids together, the researchers were in for a surprise: “Indeed, an electrical signal spread from the atrium to the left and then the right ventricular chambers — just like in early fetal heart development in animals,” Mendjan recalls. “We now observed this fundamental process in a human heart model for the first time, with all its chambers.”
While the previous Cardioid model allowed the researchers to study the chamber’s shape and tissue organization, the newly developed multi-chamber Cardioids enabled them to go beyond, studying how regional gene expression differences lead to specific chamber contraction patterns and intricate communication between them.
The researchers have already gained insight into early heart development, particularly how the human heart starts beating — which has not been understood so far. “We saw that as the organoid chambers developed, they performed an intricate dance of lead and follow. At first, the left ventricular chamber leads the budding right ventricular and atrium chambers at its rhythm. Then, as the atrium develops- two days later- the ventricles follow the atrial lead. This mirrors what is seen in animals before the final leaders, the pacemakers, control the heart rhythm,” explains Alison Deyett, a PhD student in the Mendjan group and one of the study’s first authors.
Screening platform for congenital heart disease & therapy
In addition to studying human development, multi-chamber Cardioids enable researchers to investigate chamber-specific defects. In a proof-of-principle, the Mendjan team set up a screening platform for defects, in which they study how known teratogens and mutations affect hundreds of heart organoids simultaneously.
Thalidomide, a well-known teratogen in humans, and retinoid derivatives — used in treatments against leukaemia, psoriasis, and acne — are known to cause severe heart defects in the fetus. Both teratogens induced similar, severe compartment-specific defects in the heart organoids. In a similar way, mutations in three cardiac transcription factor genes led to chamber-specific defects seen in human development. “Our tests show that multi-chamber Cardioids recapitulate embryonic heart development and can uncover disruptive effects on the whole heart with high specificity. We do this using a holistic approach, looking at multiple readouts simultaneously ,” Mendjan sums up.
In the future, multi-chamber heart organoids can be used for toxicology studies and to develop new drugs with heart chamber-specific effects. “For example, atrial arrhythmias are widespread, but we currently don’t have good drugs to treat it. One reason is that no models existed comprising all regions of the developing heart working in a coordinated manner — so far,” Mendjan adds. And although heart defects are common, including as the leading cause of miscarriages, the individual origin often remains unknown.
Heart organoids developed from patient-derived stem cells could, in the future, give insight into the developmental defect and how it may be treated and prevented. The Mendjan group is particularly interested in using multi-chamber heart organoids to understand heart development further: “We now have a basis to investigate the heart’s further growth and regenerative potential.”
IMBA has granted an exclusive license of the multi-chamber cardiac organoid technology to HeartBeat.bio AG, a spin-off company of IMBA, which Sasha Mendjan co-founded. Several researchers at HeartBeat.bio contributed scientifically to the new publication. The company has already translated IMBA’s left-ventricular Cardioid technology into a fully automated and integrated human 3D drug discovery platform tackling different forms of heart failure. The licensing of the multi-chamber model enables HeartBeat.bio to expand its portfolio of disease models further, providing more opportunities for building a cardiac drug discovery pipeline.
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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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