Daily Archives: January 22, 2025

In breakthrough, scientists find pressure sensor in fat tissue

In a video uploaded to the internet in November, Ardem Patapoutian, who shared the medicine Nobel Prize in 2021, unbuttoned his cuff and pulled up his sleeve to reveal a tattoo near his elbow. As he flexed his arm, the tattoo came to life. The tattoo was of the PIEZO mechanosensitive channel – a class of proteins that helps us sense pressure – and the flexing demonstrated how the channel opened and closed in response to pressure.If you really love your protein of interest commit to a tattoo @ardemp.bsky.social[image or embed]— Leslie B Vosshall PhD (@leslievosshall.bsky.social) 22 November 2024 at 07:59Patapoutian, a molecular biologist and neuroscientist at the Scripps Research institute, California, and Betrand Coste, then a postdoctoral researcher in Patapoutian’s lab, discovered the PIEZO ion channels in 2010.Ion channels are proteins that have a pore in their structure. In response to certain stimuli, the protein’s structure changes and the pore widens. When this happens, ions can flow through, changing the voltage across a cell’s membrane. If the cell is a neuron, it can use the resulting electric signal to communicate with other neurons. This is how the human nervous system works.The stimuli that open an ion channel are called its gates. When researchers say voltage-gated ion channels, they mean a particular channel opens when the voltage across a cell membrane changes. Since the ion channels discovered by Patapoutian and Coste were gated by pressure, they called them mechanosensitive ion channels.They discovered two such channels and named them PIEZO1 and PIEZO2, both from the Greek word ‘piezi’ meaning ‘pressure’.Since their 2010 discovery, PIEZO channels have been implicated in our ability to sense touch and pain, to understand how our bodies are positioned in space (proprioception), to perceive our body’s internal state (interoception), and to respire, urinate, form blood vessels, regulate bone density, and heal skin wounds.Two new studies — which independent experts called “pivotal” and a “breakthrough” to this reporter — have now expanded the ambit of PIEZO channels’ functions.One, a preprint from the labs of Patapoutian and his colleague at Scripps Research, Li Ye, demonstrates the role PIEZO2 plays in sensing mechanical changes in fat tissue. The second study, published in the journal Science and led by Danijela Matic Vignjevic from the Curie Institute in Paris and Tae-Hee Kim from the University of Toronto, shows the importance of the two PIEZO channels in regulating the fate of stem cells in mouse intestines.The papers lend credence to the idea that biochemical cues don’t have a monopoly on regulating biological processes: many of them involve mechanical stimuli as well. The findings open “intriguing avenues for future research,” Namrata Gundiah, a professor of mechanical engineering at the Indian Institute of Science (IISc), Bengaluru, who studies how mechanical stimuli affect the movement of cells, said.‘What is it sensing in fat?’The fat, or adipose, tissues in our bodies need to communicate with the brain to adjust the body’s metabolism. Typically, scientists study how the brain communicates with adipose tissue through the sympathetic nervous system and how the adipose tissue replies through circulating chemical signals.But the new Patapoutian et al. study, which is awaiting peer-review, focused on a different link between the brain and adipose tissue: sensory afferents.Neurons are a type of cells that make up our nervous system. Each neuron has two main parts: a cell body and a tail-like extension called the axon. The spinal cord has some cell clusters called the dorsal root ganglia (DRG). The axons of the neurons in these clusters are called sensory afferents. They enter tissues and sense various stimuli.The researchers injected adipose tissues in mice with cholera toxin-B (CTB) that had been bound to molecules that could glow if hit with light. CTB is a part of the cholera toxin, a set of proteins produced by the bacterium Vibrio cholerae. These proteins bind to certain compounds on the membranes of neurons. By injecting CTB in mice adipose tissues, the team could identify these tissues using the glow molecules and isolate them.When the team looked for the most abundant ion channels in these neurons, they found an unexpected candidate: PIEZO2.PIEZO2 is known to be a specialised mechanosensitive ion channel: it is gated only by pressure, not other factors. It is thus safe to say these sensory afferents are sensing mechanical changes in adipose tissues.Gautam Menon, a professor of physics and biology at Ashoka University who studies how cells sense and respond to mechanical forces, called this “a major discovery”.One question, however, remains unanswered: what is the source of these mechanical changes? As Patapoutian remarked on the social media platform Bluesky, “What is it sensing in fat?”Preprint dropped! Excited about this study by Yu Wang, a PhD student from Li Ye’s lab and mine, now a postdoc in @deisseroth.bsky.social lab. It unveils an unexpected role for PIEZO2/mechanosensation in sensory neurons that innervate fat! What is it sensing in fat?www.biorxiv.org/content/10.1…[image or embed]— Ardem Patapoutian (@ardemp.bskyverified.social) 20 November 2024 at 08:10Scientists don’t have an answer yet — but the rest of the study shows a way. When the team used genetic techniques to reduce the levels of PIEZO2 proteins in sensory afferents, they found that parts of the adipose tissue innervated by these afferents had larger cells. These parts also more expressed genes involved in metabolic processes that help the body produce heat and convert carbohydrates, proteins, and alcohol into fat. These changes have been previously reported to result from the removal of DRG — where the sensory afferents are rooted — in mice.The researchers also showed that if the levels of PIEZO2 are artificially increased in mice whose DRGs have been removed, the changes of such removal can be reversed.Taken together, the experiments suggest that different metabolic processes in adipose tissue cause mechanical changes in the tissue. The sensory afferents sense these mechanical changes through PIEZO channels and communicate them to the brain.A gut feelingIn 1745, German physician Johann Nathanel Lieberkühn described in detail glands found between finger-like projections called villi in the small intestine. These glands house intestinal stem cells (ISCs) that have the ability to develop into other cell types required by the intestinal tract. The development process is tightly controlled and important to regenerate and maintain the gut lining.The cells of these glands are arranged in a particular pattern on a network of proteins and other molecules called the extracellular matrix. The matrix helps keep the gland tissue stiff, which is another way to say the glands are potentially capable of sensing and responding to mechanical stimuli. The ISCs also exert forces on other cells in the gland as they change into other cell types.To understand how these mechanical forces affect the ISCs, researchers in the labs of Vignjevic and Tae-Hee Kim generated 3D miniature guts, called organoids, on Petri dishes. These mini-guts replicate the structure and function of the intestines in animals, albeit in simpler fashion. The researchers then used chemicals to inhibit PIEZO channels in the mini-guts, reducing the size of the organoids, the number of glands in each organoid, and the number of ISCs.When they removed the PIEZO channels in the guts of living mice, the animals suffered from diarrhoea, showed blood in their stools, had lower body weight, and “died quickly”, Kim said. The team concluded that “PIEZO channels in intestinal epithelia are essential” to maintain “adequate intestinal architecture and homeostasis”.The ISCs in mice whose guts lacked PIEZO channels also lost their ability to reproduce more ISCs and transform into other cell types. Instead, they became cells that divided rapidly and depleted away.In subsequent experiments, the researchers modelled the mechanical forces on ISCs. In one approach, they modelled how the stiffness of the extracellular matrix changed; in the other, they studied the tension (the force exerted on an object when it is pulled) in the tissue. In the first approach, the scientists grew mini-guts — this time 2D — on artificial substrates whose stiffness they could control. Then they quantified the activation of PIEZO channels by measuring the amount of calcium in the cells of the organoids. When PIEZO channels open, they allow calcium ions to enter cells.In their paper, the team reported the PIEZO channels were “more prone to activation” on stiffer substrates. Using atomic force microscopy, they found the area of the gland where the ISCs lived was stiffer than elsewhere. The researchers concluded the PIEZO channels were important for ISCs to sense and respond to stiffness.In the second approach, the researchers engineered a “cell-stretching device” to stretch the mini-guts. At the same time they inhibited PIEZO activity using chemicals, and found that the number of ISCs dropped.Taken together, the researchers concluded that PIEZO channels help ISCs sense mechanical changes in their surroundings, which in turn regulates their behaviour.Kim said “stem cell activity is dysregulated in many gut diseases such as inflammatory bowel disease and cancer. Thus, a better understanding of the mechanistic roles of PIEZO channels would help identify novel therapies against them.”The physics of biologyFor Gautam Menon, the Science study “adds to the view that mechanical signals, as opposed to purely biochemical ones, play an important role in deciding stem cell fates.”Two decades ago, he said, the prevalent view was that the type of cells that stem cells turn into is determined only by biochemical signals in the form of small molecules. Since then, scientists have found more and more evidence that “the mechanical environment of cells and the forces that act on them” play an important role in deciding their fate, he added.As the view has changed, researchers have confronted newer — and according to Menon “harder” — questions. These include “measuring forces in a cellular context that is realistic, and figuring out how these forces produce signals that cells can interpret.”The two new studies imply the PIEZO mechanosensitive ion channels might be the answer to the latter: these channels sense mechanical forces and open in response, allowing calcium ions to flow into cells. These ions can then trigger a series of changes within the cells that determine their fate.Kim hopes the team’s study motivates other researchers to investigate the roles of PIEZO channels in stem cells of other tissues, especially when there is tissue disease. This “would be critical for the development of more effective and targeted therapies,” he said.Sayantan Datta is a science journalist and a faculty member at Krea University. Published – January 22, 2025 05:30 am IST
Read Comments
Copy link

Email

Facebook

Twitter

Telegram

LinkedIn

WhatsApp

Reddit

Remove

SEE ALL
PRINT

How fast is the brain? Scientists reveal how quickly the brain processes information

Ever wondered how fast your brain actually works? Well, scientists have just cracked the code. In an interesting new study, researchers discovered how quickly our brains process information. It turns out that the brain is actually like a supercharged computer that can zip through data and make decisions at a speed beyond our imagination. This groundbreaking discovery is not only mind-blowing but could also open the door to understanding brain disorders and improving cognitive function. From the way we react to things around us to how we make split-second decisions, this research is shedding light on the rapid-fire processes that power our thoughts. Study uncovers the surprising limitations of our brain’s information speedOur brains are constantly processing massive amounts of sensory data, with input from sights, sounds, and touch flooding in at all times. Despite this, the speed at which our brains respond is surprisingly slow when compared to the enormous amount of information our senses gather. A groundbreaking study by Jieyu Zheng and Markus Meister from the California Institute of Technology has found that the human brain processes information at roughly 10 bits per second, a fraction of the capacity of sensory cells like those in the retina, which can transmit hundreds of millions of bits per second.While this seems somewhat limiting, perhaps it results from the elaborate networks of the neurons in our brains, wired for sifting and condensing big volumes of raw data into palatable options. Whether typing or speaking, the performance remains usually around that of 10-bit per second-threshold suggesting an intrinsic quality about brain activity.Science behind the slow yet powerful human brainWhy do we have billions of neurons if our brain processes information at a relatively modest rate of 10 bits per second? A new theory suggests that while our senses handle in parallel massive amounts of data, actions such as speech or typing occur in strict sequence. Without this, the vast parallel processing capacities of the brain would be useless for many tasks. Researchers believe that earlier stages of information processing, like in the retina, filter out unnecessary data before sending key pieces to the brain. This creates an “inner” brain that processes slowly but flexibly, alongside an “outer” brain that handles the flood of raw input in parallel. Examples from high-stakes activities like esports and sports, including Tetris and StarCraft, show that while the brain may make quick, repetitive movements, only a few decisions truly matter aligning with the 10 bits/s processing rate.Also Read: Hubble telescope unveils stunning insights into Orion Nebula’s protostars

The new science of menopause: these emerging therapies could change women’s health

In late 2022, Naomi Busch, a lone physician in her book group, began fielding question after question about menopause. Members of the group had started to experience the hallmark symptoms — hot flushes, poor sleep and mood swings — and wondered what they could do about them. “They all looked at me,” says Busch, “and I was like, ‘I don’t know anything about menopause.’” She searched for knowledgeable physicians in and around Seattle, where she lives, but the few specialists were booked out for several months. Meanwhile, the women in the book group were not getting the answers that they needed from their gynaecologists or primary-care physicians. “I’m not going down quietly,” Busch remembers one woman vowing.Busch, who trained in and practised primary-care medicine, wasn’t surprised by the lack of information. “It’s not something we learn about in medical school,” she says. So Busch decided to find out everything she could about menopause. Ultimately, she passed a competency exam to become a certified practitioner through The Menopause Society, a non-profit organization based in Pepper Pike, Ohio, that provides tools and resources to health-care professionals. She’s not alone in her interest. More than 1,300 providers became certified in 2024; and more than five times as many people applied for the exam in 2024 as in 2022. The International Menopause Society, a UK-based charity, also offers a free online training programme for health-care professionals. More than 2,600 people completed the course in 2024, up from under 2,000 in 2023.Menopause research is globally underfunded. It’s time to change thatMany health-care professionals — along with society in general — regularly tell women, and transgender, non-binary and intersex people who go through menopause, to accept the misery of the transition, and the health troubles that can follow. Menopause comes with increased risks of health conditions such as cardiovascular disease, diabetes, osteoporosis and memory loss.Yet, few medical options are typically presented to people going through menopause. Sometimes, oral contraceptives are prescribed to ease symptoms and prevent unwanted pregnancies, which are still possible during the transition. But common doses and formulations can include risks, such as developing blood clots, and don’t always provide sufficient treatment, says Busch. Non-hormonal drugs, such as fezolinetant and elinzanetant, treat hot flushes — but they also have side effects. Other options include antidepressants, cognitive behavioural therapy, acupuncture and lifestyle changes, which usually go only so far in alleviating symptoms. Hormone replacement therapy, which was a routine treatment until 2002, is widely passed over, owing to a misinterpreted study1 that prompted fear of its use.The outlook for managing menopause is now starting to change, say researchers and clinicians. Treatments — both old and emerging — are offering hope. Some researchers, for example, are revisiting hormone therapy and the optimal time for treatment to start. Others are exploring the benefits of stalling the onset of menopauseAfter decades of neglect, research funding for menopause, as well as public awareness, are now on the rise. This is a notable step in what advocates hope could be a revolution in women’s health. In May 2024, the US National Institutes of Health held a round table on future directions in menopause research, and through a White House Initiative that year, the administration of then-president Joe Biden awarded US$113 million to women’s health research. Meanwhile, a groundswell of vocal advocates around the world continue to push for awareness of how menopause affects health. Actor Halle Berry has joined US senators in championing a bill that would boost menopause research; a UK-based group of women called Menopause Mandate has organized walks to raise awareness; and Menopause Solutions Africa offers workplace training programmes.It’s hard to imagine a therapeutic space that would have as much potential payoff, specialists say. Menopause affects half the population, and it interrupts a time when people are in their prime professionally.Replenishing hormones“There is renewed interest in menopause right now, and we need to take advantage,” says Stephanie Faubion, the director of Mayo Clinic’s Center for Women’s Health in Jacksonville, Florida, and medical director of The Menopause Society.For decades, what researchers are now pushing to call ‘menopausal hormone therapy’ was the gold standard of care for alleviating common symptoms of the menopause transition. Menopause occurs when the ovaries’ last eggs are depleted. Practically, it’s defined as having had no period for 12 months in a row. Although menopause can be induced by surgery or medical treatment, for most people, it happens naturally during midlife — typically between ages 45 and 55. It’s preceded by perimenopause, a period of about four to eight years when the ovaries slow their production of certain reproductive hormones. This can result in erratic fluctuations in hormone levels, launching a rollercoaster of symptoms that can continue into the postmenopausal years. Hormone therapy replenishes some of those depleted hormones, particularly oestrogen and progesterone, and so smooths out that ride. What’s more, it can stave off osteoporosis and might provide other long-term health benefits.Women’s health research lacks funding — these charts show howBut the popularity of hormone therapy plummeted in 2002 with the publication of an initial report1 from a long-term US study called the Women’s Health Initiative (WHI). Early analyses found that people who had been through menopause and who were taking oestrogen and progestin (a synthetic form of progesterone) had slightly increased risks of breast cancer, heart attack and stroke. In its wake, the number of prescriptions for postmenopausal hormone therapy dropped abruptly worldwide. In the United States, estimated rates fell from as high as 40% down to below 5%. Susan Davis, director of the Women’s Health Research Program at Monash University in Melbourne, Australia, says global rates similarly slumped.Subsequent work highlighted the substantial limitations and misinterpretation of the findings; data from subsets of participants in the WHI and other trials even revealed contradictory findings, including lowered risk of heart disease and death associated with hormone therapy, and decreased rates of breast cancer for those taking oestrogen-only therapy. Scientists have been trying to set the record straight since.Finally, in May 2024, a review2 gained traction in medical circles and the popular media. The authors, many of whom worked on the original 2002 paper, re-emphasized that the hormone formulation, dosage and route of delivery in the WHI trials differed from what is typically used today. For example, the therapy was taken only orally in the trials. Today, the use of transdermal patches can reduce concerns about the blood clots that can be associated with oral delivery. A recent shift to hormones that are identical to the ones the body makes and the prescription of lower doses of hormones might further reduce risks, the authors note. Researchers point to another important issue: most of the people enrolled in the WHI trials were at least a decade into their postmenopausal years. At that point, research suggests, the sudden renewed presence of oestrogen might cause health problems. In other words, the timing of hormone-therapy initiation might matter.Actor Halle Berry advocates for US legislation that would increase menopause research.Credit: Tom Williams/CQ-Roll Call, Inc/GettyAnd beyond managing menopause symptoms, there are long-term benefits that could outweigh any risks. Data since the late 1980s solidly back the use of menopausal hormone therapy to prevent osteoporosis in all age groups. “The big thing that was missed in this whole WHI story was the benefit of oestrogen for fracture,” says Davis. She has been investigating whether supplemental testosterone could also protect bones after menopause.For heart disease, the equation gets more complicated. If the therapy is started early, evidence suggests that it might prevent vascular disease. But, in people with vascular disease, researchers say, the therapy might worsen the condition. There are also emerging hints that well-timed therapy can benefit brain health.At present, the exact benefits and risks of the therapy remain unclear, says Davis. “Depending on how you slice and dice and cherry pick the data, I could give you any story you want to hear.” Her concern is that researchers continue to trawl big data sets without understanding the nuances and limitations of the data.Prolonging ovarian lifeGuidance for menopause management around the world remains controversial, inconsistent and changes rapidly, specialists say. Still, there is growing consensus that clinicians should “very seriously consider” hormone therapy for women within ten years of reaching menopause, or before age 60, if they have no contraindications, says JoAnn Manson, a women’s health researcher at Harvard Medical School in Boston, Massachusetts. Although more research is needed, she says that early-initiated hormone therapy might be safe and beneficial to take long term. A study3 co-authored by Davis even suggests that the benefits of initiating hormone therapy later in menopause might still outweigh the risks.How menopause reshapes the brainWearable sensors, as well as implantable bioelectronic devices, could help to identify the optimal window for starting hormone therapy by tracking hormone levels in real time. Some physicians caution against using the therapy during perimenopause because of the potential for high combined hormone levels during erratic natural fluctuations. One day, these devices might even dispense hormones on an as-needed basis.Still, some specialists point out, replacing hormones might not be enough. The ovaries are responsible for more than making oestrogen, progesterone and eggs. The small organs send chemical signals throughout the body, driving “hundreds of other factors with health benefits”, says Zev Williams, a reproductive endocrinologist at Columbia University in New York.When the ovaries fail, says Renee Wegrzyn, director of the Advanced Research Projects Agency for Health (ARPA-H), a government agency tasked with steering the White House Initiative on women’s health, “there are a lot of chronic health conditions associated with that”. So some scientists have a different idea — keep the ovaries working indefinitely.

Enjoying our latest content?
Login or create an account to continue

Access the most recent journalism from Nature’s award-winning team
Explore the latest features & opinion covering groundbreaking research

Access through your institution

or

Sign in or create an account

Continue with Google

Continue with ORCiD