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Scientific American
02-06-2025
- Health
- Scientific American
Engineered Viruses Make Neurons Glow and Treat Brain Disease
The brain is like an ecosystem—thousands of different types of cells connect to form one big, interdependent web. And just as biologists document species of plants and animals, neuroscientists have spent decades identifying different 'species' of neurons and other brain cells that support them. They've found more than 3,000 cell types spread throughout the brain, including chandelier neurons surrounded by branching arms, pyramidal neurons with far-reaching nerve fibers and star-shaped astrocytes that help neurons form new connections with one another. This newfound diversity is not only a beautiful picture for neuroscientists—it's also key to understanding how the brain works and what goes wrong in certain brain diseases. From Parkinson's disease to schizophrenia, many brain disorders stem from specific types of brain cells. 'As long as I've been doing neuroscience, it's been a goal of researchers to have brain-cell-type-targeting tools,' says Jonathan Ting of the Allen Institute, a nonprofit research center in Seattle. Now they have them in spades. In a fleet of eight studies funded by the National Institutes of Health and published last week, scientists from 29 research institutions found and tested more than 1,000 new ways to home in on specific cell types, no matter where they are in the brain. On supporting science journalism If you're enjoying this article, consider supporting our award-winning journalism by subscribing. By purchasing a subscription you are helping to ensure the future of impactful stories about the discoveries and ideas shaping our world today. The technique behind these tools uses non-disease-causing viruses (called adeno-associated viruses, or AAVs) to deliver genes directly to specific neurons. This can make the cells do almost anything. Scientists can turn them off, activate them, 'light them up like a Christmas tree' with glowing proteins or deliver gene therapies right to them, says Ting, senior author of one of the new studies. The researchers have tested the technique only in nonhuman animals, but the bulk of the tools work across mammal species and would likely work in humans, too. Similar, less-targeted AAV gene therapies are already approved for treating spinal muscular atrophy and are being tested in clinical trials for Huntington's disease. 'There are a lot of good examples' of how AAVs are being used to treat brain disease, says Nikolaus McFarland, a neurologist at the University of Florida, who treats neurodegenerative diseases such as Parkinson's and Huntington's. 'It's really exciting stuff.' Viral Shuttles Every type of brain cell is like a unique creature. Scientists have categorized the cells based on their shape, location and electrical properties—and, more generally, based on the genes they express most out of an organism's full library of DNA. By expressing certain genes, these cells carry out specific actions, such as building specialized proteins. If researchers can identify a unique snippet of genetic code that is activated just in those cells, they can use that snippet to target them. Next, they attach this genetic snippet, called an enhancer, to an AAV that has been gutted of its viral DNA. They can fill the viral husk with specific genes to deliver to those cells. The now-filled husks enter the bloodstream like a fleet of delivery shuttles, bypassing the blood-brain barrier, but are only able to activate their genetic cargo in cells with the enhancer. In the new studies, researchers focused on cell types in three parts of the brain: the outer layer of brain tissue called the cortex that plays a role in higher-level thinking, the striatum, which is part of the basal ganglia (a stretch of deep brain tissue) that is impacted in Huntington's and Parkinson's disease, and the spinal cord, whose motor neurons are destroyed in amyotrophic lateral sclerosis (ALS). The consortium of 247 scientists was funded by the NIH's Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative as a part of a larger research project called the Armamentarium for Precision Brain Cell Access. The scientists found and tested more than 1,000 enhancer AAVs, now freely available to researchers, that target specific cell types in those key brain regions. Tweaking the Brain Previously, these enhancer AAVs had been developed in a slow trickle by different labs, but 'now we have thousands of tools' to tweak specific cell types, says Bosiljka Tasic, director of molecular genetics at the Allen Institute and senior author of one of the new studies. Researchers can load these AAV shuttles with all sorts of different genes to answer different questions. In some cases, even just seeing the neurons in action is cause for celebration: 'Some of them are very rare cells that you wouldn't find randomly by poking around in brain tissue,' Ting says. To observe them, researchers can introduce a gene that makes a glowing protein that lights up elusive neurons from the inside to reveal their structure and how they connect with other brain cells. Researchers can also control how certain brain cells fire and turn their activity up or down to see how the change impacts an animal's behavior. To do this, researchers insert a gene into the target cells that creates a light-sensitive protein called an opsin; then they can shine specific wavelengths of light on the brain to make those cells fire on command. Ting's team used this technique, called optogenetics, to stimulate certain cells in the striatum of mice. When the researchers stimulated those cells on just one side of the brain, the mice began moving more on one side of their body than the other, causing them to go in circles. These interventions are reversible and repeatable. 'That's the part that's really satisfying for neuroscientists,' Ting says. 'You can turn them off, turn them back on and then see how that affects the brain circuit.' It's ' so much better and also so much more informative' than destroying whole parts of a mouse brain to see what happens, as is the case with much neuroscience research from the past century, Tasic says. 'That brain region may have a hundred different cell types,' so being able to activate and inactivate them more precisely will reveal more information about how these circuits work, she says. New Treatments So far, the new enhancer AAVs have been tested in mice, rats and macaques. 'We keep trying more and more species,' Ting says. 'We haven't even figured out what's the limit.' And that brings us to humans. 'That's really the answer to the question 'Why do we care?'' he says. 'We have built strong evidence that some of these tools—maybe not all of them, but many of them—may work across species into humans and could represent the start of a new therapeutic vector development that could be used to more finely treat debilitating brain disorders.' For these treatments, enhancer AAVs could deliver gene therapy right to the brain cells that need it. The best candidates for this technique are neurodegenerative diseases, such as ALS, Parkinson's disease and Huntington's disease. Researchers are currently working on AAV gene therapies for these conditions and others that target whole regions of the brain rather than specific types of brain cells. Trials of these therapies indicate that they are largely safe. 'We now have lots of good examples of AAV being used,' McFarland says. 'We have [a] good safety record for that.' 'There's a lot that we still don't understand about neurodegenerative diseases,' he adds, and these little viral shuttles will allow scientists to make those discoveries that enable new treatments. While each of these brain disorders is unique, cracking one of them might help scientists crack the others, too, McFarland says: 'I wholeheartedly believe that.'
Daily Mail
28-05-2025
- Business
- Daily Mail
First subtle sign of dementia that can strike 20 years before disease sets in - as experts discover the condition has a 'stealth phase'
Scientists have pinpointed subtle, telltale signs of the memory-robbing disease that can occur up to twenty years before the onslaught of classic symptoms strike. Problems with spatial awareness, like difficulty reading the sat nav or standing too close to other people, are thought to be the first signs of a future dementia diagnosis. Experts say these troubles often begin prior to the telltale brain damage appearing on scans. That's because, according to researchers from the Allen Institute for Brain Science in Seattle, the disease develops in two distinct phases, known as 'epochs'. The first so-called 'stealth' phase, which can begin decades before symptoms become obvious, involves damage to just a few vulnerable cells in the brain. And this typically happens in the part of the brain that's important for spatial navigation, Professor Michael Hornberger, dementia expert from the University of East Anglia, explained in a new report about the US research. 'This probably explains why losing your way can be among the first signs of Alzheimer's disease.' The second phase, sees a build up of the proteins tau and amyloid in the brain. Whilst most aging brains will have some level of both these proteins, a significant clump of them can for plaques and tangle—and this is thought to be behind dementia symptoms. This is when telltale signs of cognitive collapse that we commonly associate with dementia—including memory loss, language difficulties and problems with thinking and reasoning—appear. In the most recent Seattle study, scientists analysed the post-mortem brains of 84 donors, all of whom suffered Alzheimer's. The researchers used machine learning to track levels of tau and amyloid in the brain. The authors of the study found that even in donors with low levels of the problematic proteins, there were already signs of decay, with a number of crucial inhibitory neurons having been lost. Lead author Dr Mariano Gabitto, a professor of neuroscience at the institute said this decay could compound over time, resulting in further disruption, as the disease spreads to the middle temporal gyrus—the area responsible for language and memory. A previous study looking at the brain scans of more than 100 volunteers with a family history of Alzheimer's also found that those with higher levels of both proteins were more likely to suffer memory loss and shorter attention spans. Dr Gabitto explained to Science Focus: 'Identifying the earliest neurons lost could be crucial for developing therapeutic interventions to protect them and prevent further cognitive decline.' The researchers now want to ascertain whether this means they can accurately predict cognitive decline. They are confident that early intervention during the so-called 'stealth' phase could delay—or even prevent—the progression of the deadly disease. 'The disease's long pre-symptomatic and silent period creates opportunities for early detection, early intervention and even prevention of dementia symptoms,' Dr Igor Camargo Fontana, director of scientific conference programming at Alzheimer's Association, told Science Focus. Around 982,000 in the UK are thought to be living with dementia, according to Alzheimer's Association. Alzheimer's affects around six in 10 people with dementia. Memory problems, thinking and reasoning difficulties and language problems are common early symptoms of the condition, which then worsen over time. Dementia cases are expected to sky-rocket to 1.4million people by 2040, making a cheap screening tool vital to get to grips with the challenge. The disease cost the UK around £42billion in 2024 alone. The cost of dementia in the UK is forecast to be £90 billion in the next 15 years. While dementia can be caused by multiple health issues, it is most commonly triggered by Alzheimer's disease. Alzheimer's Research UK analysis found 74,261 people died from dementia in 2022 compared with 69,178 a year earlier, making it the country's biggest killer. It comes as scientists in South Korea discover a new possible cause for the early onset of the disease. Researchers found that suffering from metabolic syndrome increases a person's risk of early onset-dementia by a shocking 24 per cent. Metabolic syndrome is diagnosed when someone has three or more of the following conditions: belly fat, high blood pressure, high blood sugar, high triglycerides—a type of fat found in the blood—and low levels of 'good' cholesterol. But researchers found the risk climbed with every additional condition—people with all five had a 70 percent higher risk. Researchers didn't provide an explanation for the possible link, but obesity, high blood pressure and high blood sugar - especially in people with diabetes - have all been linked to an increased risk of dementia.
Geek Wire
21-05-2025
- Health
- Geek Wire
Researchers develop a new set of genetic tools designed to treat brain diseases
This color-coded graphic shows different populations of cells in the mouse brain, each one targeted by one of the genetic tools developed by scientists at the Allen Institute and other institutions. (Allen Institute Graphic) Scientists say they've put together a new kind of molecular toolkit that could eventually be used to treat a variety of brain diseases, possibly including epilepsy, sleep disorders and Huntington's disease. The kit currently contains more than 1,000 tools of a type known as enhancer AAV vectors, with AAV standing for 'adeno-associated virus.' A consortium that included researchers from Seattle's Allen Institute for Brain Science and the University of Washington combined harmless adeno-associated viruses with snippets of engineered DNA to create a gene-therapy package that could target specific neurons in the brain while having no effect on other cells. Researchers laid out their findings in a set of eight studies published today in the Cell Press family of journals. The work is part of a project called the Armamentarium for Precision Brain Cell Access, funded through the National Institutes of Health's BRAIN Initiative. 'Honing in on the right cells — in the right way and at the right time — is the future of precision brain medicine,' John Ngai, director of the BRAIN Initiative, said in a news release. 'These tools move us closer to that future, while also expanding what we know about the brain's cells and circuits today.' Jonathan Ting, one of the study authors and an associate investigator at the Allen Institute, noted that enhancer AAV vectors have been used before to target cells in the brain and other tissues such as the heart and liver. In March, for example, a team led by researchers at the Allen Institute and Seattle Children's Research Institute described an AAV vector that shows promise for treating Dravet syndrome, a genetic disorder that causes a severe form of epilepsy. 'What is unique about this new collection is the immense scale of new cell-type targeting tools,' Ting told GeekWire in an email. 'Rather than a trickle of tools for the purpose of advancing understanding of the brain, now we have what amounts to a tidal wave of new tools to access and perturb cell function across a remarkable diversity of cell types in multiple brain regions and the spinal cord.' Different enhancer AAV vectors were engineered to target different cell types in different regions of the central nervous system, including the spinal cord, the cortex and the striatum. That specificity could open new avenues for targeted treatment. For example, dysfunction in the striatum is linked to movement disorders such as Parkinson's and Huntington's disease — and may also play a role in drug addiction. 'There is an overall principle that diseases usually arise from flaws in specific cell types, not the whole organism. For example, epilepsy is a nervous system disease that is actually a disease of specific neurons in the nervous system,' said study author Bosiljka Tasic, director of molecular genetics at the Allen Institute. 'If you want to fix those neurons, you can try to access only those neurons. The key is this cell-type-specific access for understanding and perturbing brain cells to figure out their function, and for correcting and fixing the defective parts of these cells.' The cover of the journal Neuron features research into 'molecular switches' that can target specific types of brain cells. (Cell Press) One study documented how one of the molecular tools targeted a rare type of cell that regulates sleep. 'It is reasonable to speculate that this tool and various derivative tools could be used to better understand the central control of sleep, or to intervene in cases of sleep disturbance disorders in humans,' Ting told GeekWire. 'The exact applications remain to be determined.' The experiments described in the studies were conducted on mice, rats and macaque monkeys, plus tissue samples from those species as well as from marmosets and humans. One of the studies used machine-learning models to identify the most promising enhancer for targeting a specific region of the rhesus monkey brain. That region, known as the dorsolateral prefrontal cortex, is associated in humans with working memory and impulse control. In the short term, the new toolkit should help researchers use animal models to gain new insights into the workings of the different types of cells in the central nervous system, and learn how to switch specific functions of those cells on or off. Gordon Fishell, a professor of neurobiology at Harvard and the Broad Institute, said that gaining access to a variety of cell types will be a 'game-changer in understanding the brain and developing therapies for human neurological disorders.' It may take a while for clinical applications to emerge. 'The time horizon is unclear for how fast any of these novel approaches can advance to the clinic, but we expect to see advances along these lines relatively quickly, as in the next two to three years,' Ting said. 'This may take the form of developing a 'Version 2.0' approach to a failed Version 1.0 strategy that didn't target cell types and yielded some disappointing outcomes.' Ting and his colleagues expect to improve the safety and efficacy of their tools as they become more familiar with the toolkit. 'We expect this scenario will play out for many diverse CNS [central nervous system] disorders into the future,' he said. In addition to the Allen Institute for Brain Science and the University of Washington, the institutions collaborating in the studies published today include the Broad Institute, Harvard Medical School, Duke University, the University of California at Irvine, the University of California at Berkeley, the University of Pittsburgh, Carnegie Mellon University, Stanford University and Addgene. The tools and data in the studies are freely available on the Allen Institute's Genetic Tools Atlas and through Addgene.
Malay Mail
02-05-2025
- Health
- Malay Mail
Where does consciousness live? Scientists say it may not be in our ‘smart' brain at all
WASHINGTON, May 3 — Consciousness is at the centre of human existence, the ability to see, hear, dream, imagine, feel pain or pleasure, dread, love and more. But where precisely does this reside in the brain? That is a question that has long confounded scientists and clinicians. A new study is offering fresh insight. In a quest to identify the parts of the brain underpinning consciousness, neuroscientists measured electrical and magnetic activity as well as blood flow in the brains of 256 people in 12 laboratories across the United States, Europe and China, while the participants viewed various images. The measurements tracked activation in various parts of the brain. The researchers found that consciousness may not arise in the 'smart' part of the brain — the frontal areas where thinking is housed, which progressively grew in the process of human evolution — but rather in the sensory zones at the back of the brain that process sight and sound. 'Why is any of this important?' asked neuroscientist Christof Koch of the Allen Institute in Seattle, one of the leaders of the study published this week in the journal Nature. 'If we want to understand the substrate of consciousness, who has it — adults, pre-linguistic children, a second trimester foetus, a dog, a mouse, a squid, a raven, a fly — we need to identify the underlying mechanisms in the brain, both for conceptual reasons as well as for clinical ones,' Koch said. The subjects in the study were shown images of people's faces and various objects. 'Consciousness is the way it feels like to see a drawing of a toaster or Jill's face. Consciousness is not the same as the behaviour associated with this feeling, for example pushing a button or saying, 'I see Jill,'' Koch said. The researchers tested two leading scientific theories about consciousness. Under the Global Neuronal Workspace Theory, consciousness materialises in the front of the brain, with important pieces of information then broadcast widely throughout the brain. Under the Integrated Information Theory, consciousness emanates from the interaction and cooperation of various parts of the brain as they work collectively to integrate information that is consciously experienced. The findings did not square with either theory. 'Where are the neuronal footprints of consciousness in the brain? Very crudely put, are they in the front of the cortex — the outermost layer of the brain — such as the prefrontal cortex, as predicted by the Global Neuronal Workspace Theory?' Koch asked. It is this prefrontal cortex that makes our species uniquely human, driving higher-order cognitive processes such as planning, decision-making, reasoning, personality expression, and moderating social behaviour. 'Or are the footprints in the back regions of the cortex, the posterior cortex?' Koch asked. The posterior cortex houses the regions where hearing and vision processing occurs. 'Here, the evidence is decidedly in favour of the posterior cortex. Either information pertaining to the conscious experience couldn't be found in the front or it was far weaker than in the back. This supports the idea that while the frontal lobes are critical to intelligence, judgment, reasoning, etc., they are not critically involved in seeing, in conscious visual perception,' Koch said. However, the study did not identify enough connections that last for as long as the conscious experience in the back of the brain to uphold the Integrated Information Theory. There are practical applications in gaining a deeper understanding of the mechanics of consciousness in the brain. Koch said it would be important for how doctors deal with patients in a coma or patients in a vegetative state or with unresponsive wakefulness syndrome, when they are awake but present no signs of awareness due to traumatic brain injury, stroke, cardiac arrest, a drug overdose or other causes. 'If the patient remains in this unresponsive state for longer than a few days without signs of recovery, the clinical team initiates discussion with the family around, 'Is this what they would have wanted?'' Koch said. Of such patients, 70 per cent to 90 per cent die because a decision has been made to withdraw life-sustaining treatment. 'However, we now know that around a quarter of patients in either coma or vegetative state/unresponsive wakefulness syndrome are conscious — covert consciousness — yet are unable to signal this at the bedside,' Koch said, referring to research published last year in the New England Journal of Medicine. 'Knowing about the footprints of consciousness in the brain will let us better detect this covert form of 'being there' without being able to signal.' — Reuters
Asharq Al-Awsat
01-05-2025
- Health
- Asharq Al-Awsat
Scientists Explore Where Consciousness Arises in the Brain
Consciousness is at the center of human existence, the ability to see, hear, dream, imagine, feel pain or pleasure, dread, love and more. But where precisely does this reside in the brain? That is a question that has long confounded scientists and clinicians. A new study is offering fresh insight. In a quest to identify the parts of the brain underpinning consciousness, neuroscientists measured electrical and magnetic activity as well as blood flow in the brains of 256 people in 12 laboratories across the United States, Europe and China, while the participants viewed various images. The measurements tracked activation in various parts of the brain. The researchers found that consciousness may not arise in the "smart" part of the brain - the frontal areas where thinking is housed, which progressively grew in the process of human evolution - but rather in the sensory zones at the back of the brain that process sight and sound. "Why is any of this important?" asked neuroscientist Christof Koch of the Allen Institute in Seattle, one of the leaders of the study published this week in the journal Nature. "If we want to understand the substrate of consciousness, who has it - adults, pre-linguistic children, a second trimester fetus, a dog, a mouse, a squid, a raven, a fly - we need to identify the underlying mechanisms in the brain, both for conceptual reasons as well as for clinical ones," Koch said. The subjects in the study were shown images of people's faces and various objects. "Consciousness is the way it feels like to see a drawing of a toaster or Jill's face. Consciousness is not the same as the behavior associated with this feeling, for example pushing a button or saying, 'I see Jill,'" Koch said. The researchers tested two leading scientific theories about consciousness. Under the Global Neuronal Workspace Theory, consciousness materializes in the front of the brain, with important pieces of information then broadcast widely throughout the brain. Under the Integrated Information Theory, consciousness emanates from the interaction and cooperation of various parts of the brain as they work collectively to integrate information that is consciously experienced. The findings did not square with either theory. "Where are the neuronal footprints of consciousness in the brain? Very crudely put, are they in the front of the cortex - the outermost layer of the brain - such as the prefrontal cortex, as predicted by the Global Neuronal Workspace Theory?" Koch asked. It is this prefrontal cortex that makes our species uniquely human, driving higher-order cognitive processes such as planning, decision-making, reasoning, personality expression, and moderating social behavior. "Or are the footprints in the back regions of the cortex, the posterior cortex?" Koch asked. The posterior cortex houses the regions where hearing and vision processing occurs. "Here, the evidence is decidedly in favor of the posterior cortex. Either information pertaining to the conscious experience couldn't be found in the front or it was far weaker than in the back. This supports the idea that while the frontal lobes are critical to intelligence, judgment, reasoning, etc., they are not critically involved in seeing, in conscious visual perception," Koch said. However, the study did not identify enough connections that last for as long as the conscious experience in the back of the brain to uphold the Integrated Information Theory. There are practical applications in gaining a deeper understanding of the mechanics of consciousness in the brain. Koch said it would be important for how doctors deal with patients in a coma or patients in a vegetative state or with unresponsive wakefulness syndrome, when they are awake but present no signs of awareness due to traumatic brain injury, stroke, cardiac arrest, a drug overdose or other causes. "If the patient remains in this unresponsive state for longer than a few days without signs of recovery, the clinical team initiates discussion with the family around, 'Is this what they would have wanted?'" Koch said. Of such patients, 70% to 90% die because a decision has been made to withdraw life-sustaining treatment. "However, we now know that around a quarter of patients in either coma or vegetative state/unresponsive wakefulness syndrome are conscious - covert consciousness - yet are unable to signal this at the bedside," Koch said, referring to research published last year in the New England Journal of Medicine. "Knowing about the footprints of consciousness in the brain will let us better detect this covert form of 'being there' without being able to signal."
