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First multi-chamber heart organoids unravel human heart development and disease

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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.

Cardiovascular disease is the leading cause of death worldwide, but only a few new therapies are on the horizon. Similarly, one in every 50 babies born suffers from a congenital heart defect — and again, therapies are few and far between, as we know little why they arise. What is missing in understanding both heart disease and cardiac malformations is a model comprising the major regions of the human heart. Now, the Mendjan team at IMBA presents the first physiological organoid model that includes all the principal developing heart structures and allows researchers to study cardiac disease and development.

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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AI headphones let wearer listen to a single person in a crowd, by looking at them just once

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AI headphones let wearer listen to a single person in a crowd, by looking at them just once


Noise-canceling headphones have gotten very good at creating an auditory blank slate. But allowing certain sounds from a wearer’s environment through the erasure still challenges researchers. The latest edition of Apple’s AirPods Pro, for instance, automatically adjusts sound levels for wearers — sensing when they’re in conversation, for instance — but the user has little control over whom to listen to or when this happens.

A University of Washington team has developed an artificial intelligence system that lets a user wearing headphones look at a person speaking for three to five seconds to “enroll” them. The system, called “Target Speech Hearing,” then cancels all other sounds in the environment and plays just the enrolled speaker’s voice in real time even as the listener moves around in noisy places and no longer faces the speaker.

The team presented its findings May 14 in Honolulu at the ACM CHI Conference on Human Factors in Computing Systems. The code for the proof-of-concept device is available for others to build on. The system is not commercially available.

“We tend to think of AI now as web-based chatbots that answer questions,” said senior author Shyam Gollakota, a UW professor in the Paul G. Allen School of Computer Science & Engineering. “But in this project, we develop AI to modify the auditory perception of anyone wearing headphones, given their preferences. With our devices you can now hear a single speaker clearly even if you are in a noisy environment with lots of other people talking.”

To use the system, a person wearing off-the-shelf headphones fitted with microphones taps a button while directing their head at someone talking. The sound waves from that speaker’s voice then should reach the microphones on both sides of the headset simultaneously; there’s a 16-degree margin of error. The headphones send that signal to an on-board embedded computer, where the team’s machine learning software learns the desired speaker’s vocal patterns. The system latches onto that speaker’s voice and continues to play it back to the listener, even as the pair moves around. The system’s ability to focus on the enrolled voice improves as the speaker keeps talking, giving the system more training data.

The team tested its system on 21 subjects, who rated the clarity of the enrolled speaker’s voice nearly twice as high as the unfiltered audio on average.

This work builds on the team’s previous “semantic hearing” research, which allowed users to select specific sound classes — such as birds or voices — that they wanted to hear and canceled other sounds in the environment.

Currently the TSH system can enroll only one speaker at a time, and it’s only able to enroll a speaker when there is not another loud voice coming from the same direction as the target speaker’s voice. If a user isn’t happy with the sound quality, they can run another enrollment on the speaker to improve the clarity.

The team is working to expand the system to earbuds and hearing aids in the future.

Additional co-authors on the paper were Bandhav Veluri, Malek Itani and Tuochao Chen, UW doctoral students in the Allen School, and Takuya Yoshioka, director of research at AssemblyAI. This research was funded by a Moore Inventor Fellow award, a Thomas J. Cabel Endowed Professorship and a UW CoMotion Innovation Gap Fund.



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Birth of universe’s earliest galaxies observed for first time

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Birth of universe’s earliest galaxies observed for first time


Using the James Webb Space Telescope, University of Copenhagen researchers have become the first to see the formation of three of the earliest galaxies in the universe, more than 13 billion years ago. The sensational discovery contributes important knowledge about the universe and is now published in the journal Science.

For the first time in the history of astronomy, researchers at the Niels Bohr Institute have witnessed the birth of three of the universe’s absolute earliest galaxies, somewhere between 13.3 and 13.4 billion years ago.

The discovery was made using the James Webb Space Telescope, which brought these first ‘live observations’ of formative galaxies down to us here on Earth.

Through the telescope, researchers were able to see signals from large amounts of gas that accumulate and accrete onto a mini-galaxy in the process of being built. While this is how galaxies are formed according to theories and computer simulations, it had never actually been witnessed.

“You could say that these are the first ‘direct’ images of galaxy formation that we’ve ever seen. Whereas the James Webb has previously shown us early galaxies at later stages of evolution, here we witness their very birth, and thus, the construction of the first star systems in the universe,” says Assistant Professor Kasper Elm Heintz from the Niels Bohr Institute, who led the new study.

Galaxies born shortly after the Big Bang

The researchers estimate the birth of the three galaxies to have occurred roughly 400-600 million years after the Big Bang, the explosion that began it all. While that sounds like a long time, it corresponds to galaxies forming during the first three to four percent of the universe’s 13.8-billion-year overall lifetime.

Shortly after the Big Bang, the universe was an enormous opaque gas of hydrogen atoms — unlike today, where the night sky is speckled with a blanket of well-defined stars.

“During the few hundred million years after the Big Bang, the first stars formed, before stars and gas began to coalesce into galaxies. This is the process that we see the beginning of in our observations,” explains Associate Professor Darach Watson.

The birth of galaxies took place at a time in the history of the universe known as the Epoch of Reionization, when the energy and light of some of the first galaxies broke through the mists of hydrogen gas.

It is precisely these large amounts of hydrogen gas that the researchers captured using the James Webb Space Telescope’s infrared vision. This is the most distant measurement of the cold, neutral hydrogen gas, which is the building block of the stars and galaxies, discovered by scientific researchers to date.

Adds to the understanding of our origins

The study was conducted by Kasper Elm Heintz, in close collaboration with, among others, research colleagues Darach Watson, Gabriel Brammer and PhD student Simone Vejlgaard from the Cosmic Dawn Center at the University of Copenhagen’s Niels Bohr Institute — a center whose stated goal is to investigate and understand the dawn of the universe. This latest result brings them much closer to doing just that.

The research team has already applied for more observation time with the James Webb Space Telescope, with hopes of expanding upon their new result and learning more about the earliest epoch in the formation of galaxies.

“For now, this is about mapping our new observations of galaxies being formed in even greater detail than before. At the same time, we are constantly trying to push the limit of how far out into the universe we can see. So, perhaps we’ll reach even further,” says Simone Vejlgaard.

According to the researcher, the new knowledge contributes to answering one of humanity’s most basic questions.

“One of the most fundamental questions that we humans have always asked is: ‘Where do we come from?’. Here, we piece together a bit more of the answer by shedding light on the moment that some of the universe’s first structures were created. It is a process that we’ll investigate further, until hopefully, we are able to fit even more pieces of the puzzle together,” concludes Associate Professor Gabriel Brammer.

The study was conducted by researchers Kasper E. Heintz, Darach Watson, Gabriel Brammer, Simone Vejlgaard, Anne Hutter, Victoria B. Strait, Jorryt Matthee, Pascal A. Oesch, Pall Jakobsson, Nial R. Tanvir, Peter Laursen, Rohan P. Naidu, Charlotte A. Mason, Meghana Killi, Intae Jung, Tiger Yu-Yang Hsiao, Abdurro’uf, Dan Coe, Pablo Arrabal Haro, Steven L. Finkelstein, & Sune Toft.

The Danish portion of the research is funded by the Danish National Research Foundation and the Carlsberg Foundation.

HOW THEY DID IT

Researchers were able to measure the formation of the universe’s first galaxies by using sophisticated models of how light from these galaxies was absorbed by the neutral gas located in and around them. This transition is known as the Lyman-alpha transition.

By measuring the light, the researchers were able to distinguish gas from the newly formed galaxies from other gas. These measurements were only possible thanks to the James Webb Space Telescope’s incredibly sensitive infrared spectrograph capabilities.

ABOUT THE EARLY UNIVERSE

The universe began its “life” about 13.8 billion years ago in an enormous explosion — the Big Bang. The event gave rise to an abundance of subatomic particles such as quarks and electrons. These particles aggregated to form protons and neutrons, which later coalesced into atomic nuclei. Roughly 380,000 years after the Big Bang, electrons began to orbit atomic nuclei, and the simplest atoms of the universe gradually formed.

The first stars were formed after a few hundred million years. And within the hearts of these stars, the larger and more complex atoms that we have around us were formed.

Later, stars coalesced into galaxies. The oldest galaxies known to us were formed about 3-400 million years after the Big Bang. Our own solar system came into being about 4.6 billion years ago — more than 9 billion years after the Big Bang.



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Scientists map networks regulating gene function in the human brain

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Scientists map networks regulating gene function in the human brain


A consortium of researchers has produced the largest and most advanced multidimensional maps of gene regulation networks in the brains of people with and without mental disorders. These maps detail the many regulatory elements that coordinate the brain’s biological pathways and cellular functions. The research, supported the National Institutes of Health (NIH), used postmortem brain tissue from over 2,500 donors to map gene regulation networks across different stages of brain development and multiple brain-related disorders.

“These groundbreaking findings advance our understanding of where, how, and when genetic risk contributes to mental disorders such as schizophrenia, post-traumatic stress disorder, and depression,” said Joshua A. Gordon, M.D., Ph.D., director of NIH’s National Institute of Mental Health (NIMH). “Moreover, the critical resources, shared freely,willhelp researchers pinpoint genetic variants that are likely to play a causal role in mental illnesses and identify potential molecular targets for new therapeutics.”

The research is published across 15 papers in Science, Science Advances, and Scientific Reports. The papers report findings along several key themes:

  • Population-level analyses that link genetic variants, regulatory elements, and different molecular forms of expressed genes to regulatory networks at the cellular level, in both the developing brain and adult brain
  • Single-cell-level maps of the prefrontal cortex from individuals diagnosed with mental disorders and neurodevelopmental disorders
  • Experimental analyses validating the function of regulatory elements and genetic variants associated with quantitative trait loci (segments of DNA that are linked with observable traits)

The analyses expand on previous findings, exploring multiple cortical and subcortical regions of the human brain. These brain areas play key roles in a range of essential processes, including decision-making, memory, learning, emotion, reward processing, and motor control.

Approximately 2% of the human genome is composed of genes that code for proteins. The remaining 98% includes DNA segments that help regulate the activity of those genes. To better understand how brain structure and function contribute to mental disorders, researchers in the NIMH-funded PsychENCODE Consortium are using standardized methods and data analysis approaches to build a comprehensive picture of these regulatory elements in the human brain.

In addition to these discoveries, the papers also highlight new methods and tools to help researchers analyze and explore the wealth of data produced by this effort. These resources include a web-based platform offering interactive visualization data from diverse brain cell types in individuals with and without mental disorders, known as PsychSCREEN. Together, these methods and tools provide a comprehensive, integrated data resource for the broader research community.

The papers focus on the second phase of findings from the PsychENCODE Consortium. This effort aims to advance our understanding of how gene regulation impacts brain function and dysfunction.

“These PsychENCODE Consortium findings shed new light on how gene risk maps onto brain function across developmental stages, brain regions, and disorders,” said Jonathan Pevsner, Ph.D., chief of the NIMH Genomics Research Branch. “The work lays a strong foundation for ongoing efforts to characterize regulatory pathways across disorders, elucidate the role of epigenetic mechanisms, and increase the ancestral diversity represented in studies.”

The PsychENCODE papers published in Science and Science Advances are presented as a collection on the Science website.



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