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Alzheimer’s disease is partly genetic − studying the genes that delay decline in some may lead to treatments for all

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Alzheimer’s disease is partly genetic − studying the genes that delay decline in some may lead to treatments for all

Researchers are zeroing in on understanding what goes awry in the brains of people with Alzheimer’s disease.
Tek Image/Science Photo Library via Getty Images

Steven DeKosky, University of Florida

Diseases that in families usually have genetic causes. Some are genetic mutations that directly cause the disease if inherited. Others are risk genes that affect the body in a way that increases the someone will develop the disease. In Alzheimer’s disease, genetic mutations in any of three specific genes can cause the disease, and other risk genes either increase or decrease the risk of developing Alzheimer’s.

Some genetic mutations or variants interact with other genetic alterations that lead to Alzheimer’s disease. In some cases, gene alterations can interact with Alzheimer’s-causing genetic variants in a way that proves beneficial; they actually suppress the pathological brain changes the other mutations would normally lead to. These protective gene variants can drastically slow or prevent cognitive decline. In two recent case reports on familial Alzheimer’s disease, mutations delayed Alzheimer’s symptoms for decades.

I am a neurologist and neuroscientist who has spent my career studying Alzheimer’s disease and dementia both in the laboratory and in the clinic. Determining how genes affect brain chemistry is vital to understanding how Alzheimer’s disease progresses and devising interventions to prevent or delay cognitive decline.

The amyloid hypothesis

In the early 1990s, scientists proposed the amyloid hypothesis to explain how Alzheimer’s disease develops. The first neuropathological changes detected in the brain of Alzheimer’s disease were the formation of amyloid plaques – clumps of protein pieces called beta-amyloid. Other changes in the Alzheimer’s brain, such as the accumulation of another type of abnormal protein called neurofibrillary tangles, were thought to develop later in the course of the disease.

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Beta-amyloid begins to accumulate in the brain up to 15 years before symptoms emerge. Symptoms correlate with the number of neurofibrillary tangles in the brain – the more tangles, the worse the cognition. Researchers have tried to determine whether preventing or removing amyloid plaques from the brain would be an effective treatment.

Alzheimer’s disease results from the accumulation of abnormal proteins in the brain.

Imagine the excitement of the scientific community in the 1990s when researchers identified three different genes causing familial Alzheimer’s disease – and all three were involved with beta-amyloid.

The first was the amyloid precursor protein gene. This gene directs cells to produce the amyloid precursor protein, which breaks down into smaller fragments, the beta-amyloid that forms amyloid plaques in the brain.

The second gene was termed presenilin 1, or PSEN-1, a protein needed to cut the precursor protein into beta-amyloid.

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The third gene, presenilin 2, or PSEN-2, is closely related to PSEN-1 but found in a smaller number of families with familial Alzheimer’s disease.

These findings added strength to the amyloid hypothesis explanation of the disease. However, uncertainty and opposition to the amyloid hypothesis have developed over the past several decades. This was in part tied to a recognition that several other processes – neurofibrillary tangles, inflammation and immune system activation – are also involved in the neurodegeneration seen in Alzheimer’s.

The hypothesis also got significant pushback after many clinical trials attempting to block the effects of amyloid or it from the brain were unsuccessful. In some cases, treatments had significant side effects. Some researchers have come up with strong defenses of the hypothesis. But until a clinical trial based on the amyloid hypothesis could show definitive results, uncertainty would remain.

Genetic discoveries with treatment implications

The vast majority – more than 90% – of Alzheimer’s cases occur in late life, with disease prevalence increasing progressively from age 65 and up. Such cases are mostly sporadic, with no clear history of Alzheimer’s.

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However, a relatively small number of families have one of the three known genetic mutations that cause the disease to be passed down. In familial Alzheimer’s, 50% of each generation will inherit the mutated gene and develop the disease much earlier, usually from their 30s to early 50s.

In 2019 and 2023, researchers identified changes in at least two other genes that markedly delayed the onset of disease symptoms in people with familial Alzheimer’s disease mutations. These mutated genes were found in a very large family in Colombia whose members tended to develop Alzheimer’s symptoms by their 40s.

A woman in the family carrying a mutated PSEN-1 gene did not have any cognitive symptoms until she was in her 70s. A genetic analysis showed that she had an additional mutation in a variant of the gene that codes for a protein called apolipoprotein E, or ApoE. Researchers believe the mutation, called the Christchurch variant – named after the in New Zealand where the mutation was first discovered – is responsible for interfering with and slowing down her disease.

Importantly, her brain had a great deal of amyloid plaque but very few neurofibrillary tangles. This suggests that the link between the two was broken and that the suppressed number of neurofibrillary tangles also slowed down cognitive loss.

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Researchers have studied certain families in Colombia with rare genetic variants that slow the progression of Alzheimer’s disease.

In May 2023, researchers reported that two siblings in the same large family also did not develop memory problems until their 60s or late 70s and were found to carry a mutation in a gene that codes for a protein called reelin. Studies in mice suggest that reelin has protective effects against amyloid plaque deposition in the brain. In these patients’ brains, as with the patient who had the Christchurch variant, there were extensive amyloid plaques but very few neurofibrillary tangles. This observation confirmed that the tangles are responsible for the cognitive loss and that there are several ways to “disconnect” amyloid and neurofibrillary tangle accumulation.

Finding medicines that might mimic the protective effects of the Christchurch variant or the reelin mutation could help delay Alzheimer’s disease symptoms for all patients. Since the vast majority of nonfamilial Alzheimer’s manifests after age 70 or 75, a 10-year delay in the emergence of first symptoms of Alzheimer’s could have a massive effect in decreasing the prevalence of the disease.

These findings demonstrate that Alzheimer’s can be slowed and will hopefully lead to additional new therapies that can someday not only treat the disease but prevent it as well.

Starts and stops

Despite over 20 years of doubts and therapy failures, the past several years have seen positive results from three different treatments – aducanumab, lecanemab and donanemab – that remove amyloid plaques and slow loss of cognitive function to some extent. Although there is still discussion of how much slowing of decline is clinically significant, these successes for the amyloid hypothesis. They also suggest that other strategies will be needed for optimal treatment.

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The FDA approved the Alzheimer’s drug aducanumab (Aduhelm) in June 2021, to much controversy.

The U.S. Food and Drug Administration’s 2021 approval of the first antibody treatment for Alzheimer’s, aducanumab, sold under the brand name Aduhelm, was controversial. Only one of the two clinical trials testing its safety and effectiveness in people yielded positive results. The FDA approved the drug on the basis of that single study through an accelerated approval process in which treatments meeting an unmet clinical need can expedited approval.

The second antibody, lecanemab, sold as Leqembi, was approved in January 2023 via the same accelerated approval pathway. It was then fully approved in July 2023.

The third antibody, donanemab, completed a successful phase three clinical trial and is awaiting more safety data. When that is submitted to the FDA, the agency will consider the drug for approval.The Conversation

Steven DeKosky, Professor of Neurology and Neuroscience, University of Florida

This article is republished from The Conversation under a Creative Commons license. Read the original article.

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The Conversation

The Boeing Starliner has returned to Earth without its crew – a former astronaut details what that means for NASA, Boeing and the astronauts still up in space

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theconversation.com – Michael E. Fossum, Vice President, A&M University – 2024-09-07 10:41:12

The Boeing Starliner, shown as it approached the International Station.
NASA via AP

Michael E. Fossum, Texas A&M University

Boeing’s crew transport space capsule, the Starliner, returned to Earth without its two-person crew right after midnight Eastern time on Sept. 7, 2024. Its remotely piloted return marked the end of a fraught test flight to the International Space Station which left two astronauts, Butch Wilmore and Sunita “Suni” Williams, on the station for months longer than intended after thruster failures led NASA to deem the capsule unsafe to pilot back.

Wilmore and Williams will stay on the International Space Station until February 2025, when they’ll return to Earth on a SpaceX Dragon capsule.

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The Conversation U.S. asked former commander of the International Space Station Michael Fossum about NASA’s to return the craft uncrewed, the future of the Starliner program and its crew’s extended stay at the space station.

What does this decision mean for NASA?

NASA awarded contracts to both Boeing and SpaceX in 2014 to crew transport vehicles to the International Space Station via the Commercial Crew Program. At the start of the program, most bets were on Boeing to take the lead, because of its extensive aerospace experience.

However, SpaceX moved very quickly with its new rocket, the Falcon 9, and its cargo ship, Dragon. While they suffered some early failures during testing, they aggressively built, tested and learned from each failure. In 2020, SpaceX successfully launched its first test crew to the International Space Station.

Meanwhile, Boeing struggled through some development setbacks. The outcome of this first test flight is a huge disappointment for Boeing and NASA. But NASA leadership has expressed its for Boeing, and many experts, including me, believe it remains in the agency’s best interest to have more than one American crew launch system to support continued human space operations.

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NASA is also continuing its exchange partnership with Russia. This partnership provides the agency with multiple ways to get crew members to and from the space station.

As space station operations continue, NASA and its partners have enough options to get people to and from the station that they’ll always have the essential crew on the station – even if there are launch disruptions for any one of the capable crewed vehicles. Starliner as an option will with that redundancy.

The ISS, a cylindrical craft with solar panels on each side.
NASA has a few options to get astronauts up to the International Space Station.
Roscosmos State Space Corporation via AP

What does this decision mean for Boeing?

I do think Boeing’s reputation is going to ultimately suffer. The company is going head-to-head with SpaceX. Now, the SpaceX Dragon crew spacecraft has several flights under its belt. It has proven a reliable way to get to and from the space station.

It’s important to remember that this was a test flight for Starliner. Of course, the program managers want each test flight to run perfectly, but you can’t anticipate every potential problem through ground testing. Unsurprisingly, some problems cropped up – you expect them in a test flight.

The space is unforgiving. A small problem can become catastrophic in zero gravity. It’s hard to replicate these situations on the ground.

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The technology SpaceX and Boeing use is also radically different from the kind of capsule technology used in the early days of the Mercury, Gemini and Apollo programs.

NASA has evolved and made strategic moves to advance its mission over the past two decades. The agency has leaned into its legacy of thinking outside the box. It was an innovative move to break from tradition and leverage commercial competitors to advance the program. NASA gave the companies a set of requirements and left it up to them to figure out how they would meet them.

What does this decision mean for Starliner’s crew?

I know Butch Wilmore and Suni Williams as rock-solid professionals, and I believe their first thoughts are about completing their mission safely. They are both highly experienced astronauts with previous long-duration space station experience. I’m sure they are taking this in stride.

Prior to joining NASA, Williams was a Naval aviator and Wilmore a combat veteran, so these two know how to face risk and accomplish their missions. This kind of unfavorable outcome is always a possibility in a test mission. I am sure they are leaning forward with a positive attitude and using their bonus time in space to advance science, technology and space exploration.

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Their families shoulder the bigger impact. They were prepared to welcome the crew home in less than two weeks and now must adjust to unexpectedly being apart for eight months.

Right now, NASA is dealing with a ripple effect, with more astronauts than expected on the space station. More people means more consumables – like food and clothing – required. The space station has supported a large crew for short periods in the past, but with nine crew members on board today, the systems have to work harder to purify recycled drinking water, generate oxygen and remove carbon dioxide from their atmosphere.

Wilmore and Williams are also consuming food, and they didn’t arrive with the clothes and other personal supplies they needed for an eight-month stay, so NASA has already started increasing those deliveries on cargo ships.

What does this decision mean for the future?

Human spaceflight is excruciatingly hard and relentlessly unforgiving. A million things must go right to have a successful mission. It’s impossible to fully understand the performance of systems in a microgravity environment until they’re tested in space.

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NASA has had numerous failures and near-misses in the quest to put Americans on the Moon. They lost the Apollo 1 crew in a fire during a preflight test. They launched the first space shuttle in 1981, and dealt with problems throughout that program’s 30-year life, including the terrible losses of Challenger and Columbia.

After having no other U.S. options for over 30 years, three different human spacecraft programs are now underway. In addition to the SpaceX Crew Dragon and the Boeing Starliner, NASA’s Orion spacecraft for the Artemis II mission, is planned to fly four astronauts around the Moon in the next couple of years.

These programs have had setbacks and bumps along the way – and there will be more – but I haven’t been this about human spaceflight since I was an 11-year-old cheering for Apollo and dreaming about putting the first human footprints on Mars.The Conversation

Michael E. Fossum, Vice President, Texas A&M University

This article is republished from The Conversation under a Creative Commons license. Read the original article.

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Space travel comes with risk − and SpaceX’s Polaris Dawn mission will push the envelope further than any private mission has before

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theconversation.com – Chris Impey, University Distinguished Professor of Astronomy, University of Arizona – 2024-09-06 07:30:06

Spacewalks are among the more dangerous activities associated with human spaceflight.

Ignatiev/E+ via Getty Images

Chris Impey, University of Arizona

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is an unnatural for humans. We can’t survive unprotected in a pure vacuum for more than two minutes. Getting to space involves being strapped to a barely contained chemical explosion.

Since 1961, fewer than 700 people have been into space. Private space companies such as SpaceX and Blue Origin hope to boost that number to many thousands, and SpaceX is already taking bookings for flights to Earth orbit.

I’m an astronomer who has written extensively about space travel, including a book about our future off-Earth. I think a lot about the risks and rewards of exploring space.

As the commercial space industry takes off, there will be accidents and people will die. Polaris Dawn, planned to launch early in September 2024, will be a high-risk mission using only civilian astronauts. So, now is a good time to assess the risks and rewards of leaving the Earth.

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Space travel is dangerous

Most Americans vividly recall the disasters that led to the loss of 14 astronauts’ lives. Two of the five space shuttles disintegrated, Challenger in 1986 soon after launch and Columbia in 2003 on reentry.

The Challenger and Columbia accidents are two of the most prominent examples of the risk that with human spaceflight.

In total, 30 astronauts and cosmonauts have died while training for or during space missions.

There have also been dozens of close calls. Two astronauts are currently staying on the International Space Station for an extra six months because NASA declared their Boeing Starliner vehicle unsafe for the return journey. Starliner has had many problems during its , flammable tape, stuck valves and inadequate parachute . But a critical thruster malfunction is what caused NASA to abandon it as a return vehicle.

It’s not always safe on the ground, either. In addition to the three Apollo 1 astronauts who died in a 1967 launch pad fire, about 120 people died in the launchpad explosion of an unmanned rocket in Russia in 1960, and hundreds died in 1996 when a Chinese rocket veered off course and crashed into a nearby village.

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The fatality rate of people traveling in space is about 3%. That sounds low, but it’s higher than extreme sports such as BASE jumping or jumping off a cliff wearing a wingsuit. The only recreations that rival the risk of space travel are solo free-climbing and climbing above 19,685 feet (6,000 meters) in the Himalayas.

Civilians in space

The 2020s have kicked off the era of civilian astronauts. After the death of Christa McAuliffe in the Challenger disaster, NASA stopped sending civilians into space. But for commercial space companies, it’s part of the business model.

The first all-civilian crew to reach orbit rode a SpaceX Dragon spacecraft in 2021, the Inspiration 4 mission. Since 2020, 69 private astronauts have gone to space, although only 46 reached the Kármán line – the formal definition of the edge of space.

The commercial space industry’s safety record is not perfect. No civilian has died in space, but one pilot died and another was seriously injured in a test flight of Virgin Galactic’s SpaceShipTwo craft in 2014. This accident followed three deaths and three injuries in an explosion during a prelaunch test of the SpaceShipTwo rocket in 2007.

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SpaceX, the largest commercial space company with 13,000 employees and a market value of US$180 billion, has seen no fatalities in flight, but it has recorded one death and hundreds of injuries in the workplace.

The Polaris Dawn mission was planned to launch Aug. 27, 2024, though a helium leak and bad weather has delayed it. It will push the envelope of risk for civilians in space. This SpaceX flight will reach an altitude of 435 miles (700 kilometers), higher than any astronauts since Apollo.

Four astronauts wearing white suits and helmets stand in front of a rocket on a launchpad.

The Polaris Dawn crew during their launch-day rehearsal.

Polaris Program/John Kraus, CC BY-NC-ND

The Polaris Dawn’s four-person civilian crew will receive a hefty dose of radiation, getting as much in a few hours as they would in 20 years on the Earth. NASA is doing research to understand the extent of the health risks from radiation.

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The mission will also include a spacewalk – the first for nongovernment astronauts. It will use spacesuits never tested in space. Since the spacecraft they’re using – the SpaceX Dragon – has no airlock, the inside of the capsule will be exposed to the vacuum of space, with all the crew members wearing spacesuits.

Russian cosmonaut Alexei Leonov nearly died during the first spacewalk in 1965, and other spacewalks have led to temporary blindness, near drowning and nearly being lost in space forever. A spacesuit is like a miniature spacecraft, and it has to withstand rapid temperature changes of hundreds of degrees when moving in and out of direct sunlight. Even a small tear or puncture can be fatal.

But while space travel comes with dangers, it also has rewards. Since Polaris Dawn will travel higher than any previous mission that did not go to the Moon, the crew will be able to do research on high-radiation environments. They will investigate the effects of spaceflight on the human body and evaluate how future deep-space travelers might diagnose and treat themselves.

A less tangible but potentially profound benefit is the overview effect – many astronauts report a feeling of awe from experiencing the Earth from space.

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Space boom

Space is booming – hopefully just metaphorically and not literally. SpaceX makes money by launching Starlink satellites and ferrying supplies and people to the International Space Station, with estimated revenues of $15 billion this year. Blue Origin sells rocket engines and has contracts with NASA.

Both companies sell rides into space to high-net-worth individuals, but that’s a small fraction of their revenues. Space tourism is not available to the masses yet. Virgin Galactic offers a short, suborbital ride for $450,000, but getting to Earth orbit will cost you $55 million.

The space tourism market was $750 million in 2023, and that’s projected to grow to $5.2 billion over the next decade. Reusable rockets have made the cost of launching a spacecraft 10 times cheaper than it was a decade ago.

For space tourism to take off with a demographic broader than multimillionaires and thrill-seekers, it needs to be safe – both in perception and in reality. Many space entrepreneurs expect space travel to follow aviation’s arc, which also started by attracting rich people and thrill-seekers.

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Since 1930, improvements in technology and safety features have lowered the number of fatal accidents in the aviation industry per million miles flown by a factor of 3,000. A more realistic target may be to make space travel as safe as driving. That’s a more lenient target, since driving is more dangerous than flying. Your annual odds of dying in a car crash are 1 in 5,000, compared with annual odds of 1 in 11 million of dying in a plane crash.

In the United States, the has kept regulations light on the commercial space industry to encourage entrepreneurs.

Elon Musk’s dreams of millions of passengers and a on Mars may not become reality. But if the cost of a jaunt to Earth’s orbit comes down to the cost of a high-end cruise, many people could experience the thrill of weightlessness and of seeing the Earth as a beautiful planet from above.The Conversation

Chris Impey, University Distinguished Professor of Astronomy, University of Arizona

This article is republished from The Conversation under a Creative Commons license. Read the original article.

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Tiny, compact galaxies are masters of disguise in the distant universe − searching for the secrets behind the Little Red Dots

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theconversation.com – Fabio Pacucci, Astrophysicist, Smithsonian Institution – 2024-09-06 07:36:33

Supermassive black holes grow by pulling in matter around them.

M. Kornmesser/ESO via AP

Fabio Pacucci, Smithsonian Institution

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Astronomers exploring the faraway universe with the James Webb Space Telescope, NASA’s most powerful telescope, have found a class of galaxies that challenges even the most skillful creatures in mimicry – like the mimic octopus. This creature can impersonate other marine animals to avoid predators. Need to be a flatfish? No problem. A sea snake? Easy.

When astronomers analyzed the first Webb images of the remote parts of the universe, they spotted a never-before-seen group of galaxies. These galaxies – some hundreds of them and called the Little Red Dots – are very red and compact, and visible only during about 1 billion years of cosmic history. Like the mimic octopus, the Little Red Dots puzzle astronomers, because they look like different astrophysical objects. They’re either massively heavy galaxies or modestly sized ones, each containing a supermassive black hole at its core.

However, one thing is certain. The typical Little Red Dot is small, with a radius of only 2% of that of the Milky Way galaxy. Some are even smaller.

As an astrophysicist who studies faraway galaxies and black holes, I am interested in understanding the nature of these little galaxies. What powers their light and what are they, really?

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Many galaxies, indicated as small, bright dots, shown against a dark backdrop.

The universe is full of countless galaxies, and the Webb telescope has helped astronomers study some of them.

NASA, ESA, CSA, STScI

The mimicking contest

Astronomers analyze the light our telescopes from faraway galaxies to assess their physical properties, such as the number of they contain. We can use the properties of their light to study the Little Red Dots and figure out whether they’re made up of lots of stars or whether they have a black hole inside them.

Light that reaches our telescopes ranges in wavelength from long radio waves to energetic gamma rays. Astronomers break the light down into the different frequencies and visualize them with a chart, called a spectrum.

Sometimes, the spectrum contains emission lines, which are ranges of frequencies where more intense light emission occurs. In this case, we can use the spectrum’s shape to predict whether the galaxy is harboring a supermassive black hole and estimate its mass.

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Similarly, studying X-ray emisson from the galaxy can reveal a supermassive black hole’s presence.

As the ultimate masters of disguise, the Little Red Dots appear as different astrophysical objects, depending on whether astronomers choose to study them using X-rays, emission lines or something else.

The information astronomers have collected so far from the Little Red Dots’ spectra and emission lines has led to two diverging models explaining their nature. These objects are either extremely dense galaxies containing billions of stars or they host a supermassive black hole.

The two hypotheses

In the stars-only hypothesis, the Little Red Dots contain massive amounts of stars – up to 100 billion stars. That’s approximately the same number of stars as in the Milky Way – a much larger galaxy.

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Imagine standing alone in a huge, empty room. This vast, quiet represents the region of the universe in the vicinity of our solar system where stars are sparsely scattered. Now, picture that same room, but packed with the entire population of China.

This packed room is what the core of the densest Little Red Dots would feel like. These astrophysical objects may be the densest stellar environments in the entire universe. Astronomers aren’t even sure whether such stellar can physically exist.

Then, there is the black hole hypothesis. The majority of Little Red Dots display clear signs of the presence of a supermassive black hole in their center. Astronomers can tell whether there’s a black hole in the galaxy by looking at large emission lines in their spectra, created by gas around the black hole swirling at high speed.

Astronomers actually estimate these black holes are too massive, with the size of their compact host galaxies.

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Black holes typically have a mass of about 0.1% of the stellar mass of their host galaxies. But some of these Little Red Dots harbor a black hole almost as massive as their entire galaxy. Astronomers call these overmassive black holes, because their existence defies the conventional ratio typically observed in galaxies.

Animation illustrating the James Webb Space Telescope’s discovery of overmassive black holes in the distant Universe. Credit: Timothy Rauch.

There’s another catch, though. Unlike ordinary black holes, those presumably present in the Little Red Dots don’t show any sign of X-ray emission. Even in the deepest, high-energy images available, where astronomers should be able to easily observe these black holes, there’s no trace of them.

Few solutions and plenty of hopes

So are these astrophysical curiosities massive galaxies with far too many stars? Or do they host supermassive black holes at their center that are too massive and don’t emit enough X-rays? What a puzzle.

With more observations and theoretical modeling, astronomers are starting to up with some possible . Maybe the Little Red Dots are composed only of stars, but these stars are so dense and compact that they mimic the emission lines typically seen from a black hole.

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Or maybe supermassive – even overmassive – black holes lurk at the cores of these Little Red Dots. If that’s the case, two models can explain the lack of X-ray emissions.

First, vast amounts of gas could float around the black hole, which would block part of the high-energy radiation emitted from the black hole’s center. Second, the black hole could be pulling in gas much faster than usual. This would produce a different spectrum with fewer X-rays than astronomers usually see.

The fact that the black holes are too big, or overmassive, might not be a problem for our understanding of the universe, but rather the best indication of how the first black holes in the universe were born. In fact, if the first black holes that ever formed were very massive – about 100,000 times the mass of the Sun – theoretical models suggest that their ratio of black hole mass to the mass of the host galaxy could stay high for a long time after formation.

So how can astronomers discover the true nature of these little specks of light that are shining at the beginning of time? As in the case of our master of disguise – the octopus – the secret resides in observing their behavior.

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Using the Webb telescope and more powerful X-ray telescopes to take additional observations will eventually uncover a feature that astronomers can attribute to only one of the two scenarios.

For example, if astronomers clearly detected X-ray or radio emission, or infrared light emitted from around where the black hole might be, they’d know the black hole hypothesis is the right one.

Just like how our marine friend can pretend to be a starfish, eventually it will move its tentacles and reveal its true nature.The Conversation

Fabio Pacucci, Astrophysicist, Smithsonian Institution

This article is republished from The Conversation under a Creative Commons license. Read the original article.

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