When climbing the world's tallest mountains, what counts as cheating?
In 1978, Austrian physician and mountaineer Oswald Oelz was a team doctor on an expedition to Mount Everest when climbers Reinhold Messner and Peter Habeler became the first people to reach its summit without supplemental oxygen. Before then, it was unthinkable that humans, unassisted, could climb 29,032 feet, the height of Everest, where due to drop in atmospheric pressure we inhale only about 30 percent of the oxygen we breath at sea level.
Almost half a century later, Oelz's grand-nephew, Austrian climbing guide Lukas Furtenbach, was the architect of a new feat atop Mount Everest. This May, four of his clients, along with five Sherpas, summited the world's tallest mountain only five days after they left London. Usually, it takes an average of 40 days of slow acclimatisation to adjust to the high altitude and scarce oxygen on Everest.
The secret to the team's lightning-fast ascent: About two weeks before the expedition, Furtenbach's clients were given xenon through a medical mask. The noble gas is sometimes used as an anaesthetic but is also thought to boost the production of erythropoietin, a hormone that stimulates red blood cell production. The idea, suggested to Furtenbach by German anaesthesiologist Michael Fries, was to artificially accelerate the acclimatisation process.
The strategy, however, immediately caused controversy in the mountaineering community. Experts on high-altitude research who spoke to National Geographic mainly questioned whether xenon could actually produce an effect strong enough to mimic acclimatisation. And earlier this year, the International Climbing and Mountaineering Federation issued a statement warning about the absence of scientific studies to prove the safety and efficacy of xenon at high altitude.
Then there's the question of whether xenon, banned in professional sport by the World Anti-Doping Agency, makes the climb up Everest so easy that it obscures the line between sportsmanship and tourism. Around 7,000 people climb Everest every year with the help of supplemental oxygen. For others, using supplemental oxygen is considered a cheap shortcut akin to utilizing sherpas and fixed-ropes. Left, a climber scales Mount Everest with the aid of supplemental oxygen. Right, oxygen tanks are seen along a section of Everest called "the Balcony" near the summit. Photograph by Matthew Irving, Nat Geo Image Collection (Top) (Left) and Photograph by Mark Fisher, Nat Geo Image Collection (Bottom) (Right)
In the world of mountaineering, there's no regulatory body governing monitoring performance-enhancing drugs, but the style of a climber's ascent still holds reputational cache. Ever since Messner and Habeler's 1978 expedition proved that even the highest mountain on Earth could be climbed without supplemental oxygen, not using it has become an essential part of pushing the limits of the human body in high altitude. Called alpine style, this form of mountaineering—embraced by elite climbers—prizes climbs done without medical aids, fixed lines, or large support teams.
In contrast, a 30-year boom in commercial expeditions has focused on making the mountains more accessible to less experienced climbers, with hundreds of feet of fixed ropes, large amounts of supplemental oxygen, and the support of Sherpas. Some tour guides who lead these large groups say the controversy ignited by xenon places unfair scrutiny on what's simply the latest of many tools making mountain climbing more accessible and safer.
American climber Adrian Ballinger, owner of Alpenglow Expeditions, thinks climbers should just be honest about the style they choose. 'Professional athletes don't use supplemental oxygen when climbing in the mountains because it makes things easier. But for recreational and non-professional climbers who hire guiding companies, it's different,' he says.
However, he draws the line at the use of xenon in mountaineering—even in commercial expeditions. 'I don't see any reason,' he says, 'to use a substance banned as doping.' Doing drugs, 29,032 feet high
Climbers have a long history of employing different drugs to survive the cold and dangerous conditions of Earth's highest peaks.
In 1953, mountaineering legend Hermann Buhl took methamphetamine pills, then known by the brand name Pervitin, to stay awake during a perilous descent after summiting the Himalayan mountain Nanga Parbat in Pakistan. (Buhl made his climb without supplementary oxygen and became the first and only person to achieve a solo first ascent of an 8,000-meter peak, famously surviving the night at 26,000 feet by standing on a tiny ledge.)
In the following decades, mountaineers experimented with both banned and legal substances, from amphetamine to Viagra. Two well-known prescription drugs, diuretic acetazolamide (commonly known as Diamox) and corticosteroid dexamethasone (Decadron) are often used to treat high-altitude conditions like acute mountain sickness or cerebral edema—but against expert recommendations, some climbers take them preventatively.
Nothing, however, works better to fight hypoxia and enhance performance at high altitude than a steady flow of supplemental oxygen. Hermann Buhl in 1953, after summiting Nanga Parba, the ninth highest mountain in world, located in Pakistan. Under the influence of the drug pervitin, a stimulant similar to methamphetamine, Buhl was able to push on to the summit after the rest of his team was forced to return to camp, making Buhl the first and only person to make a solo-ascent of an 8,000 meter peak. Photograph by Touring Club Italiano/Marka/UniversalA view of Nanga Parbat as seen from Jammu & Kashmir, 1933. Photograph by Royal Air Force/Royal'If you use supplemental oxygen continuously, oxygen delivery to tissues is maintained. You will not develop altitude illness, and exercise performance will not be affected,' explains Martin Burtscher, a long-time researcher in the field of high-altitude medicine and retired professor at the University of Innsbruck in Austria.
This is why some climbers, still devoted to purist alpine style, refrain from using supplemental oxygen, since they consider it a form of high-altitude doping.
Furtenbach adhered to this minimalist climbing style when he was younger, but over time opted for climbing aids that he says made ascents safer for him and his clients. He doesn't think new techniques should be looked down on if they make climbing in the Himalaya safer.
'If you want to climb at this altitude, you can do it in either an extremely dangerous way and risk your life, or you can try to climb as safely as possible,' says Furtenbach. 'And that means you need to use all the medical aids that are available.'
He argues that singling out xenon is hypocritical: 'If someone wants to ban xenon from mountaineering, then it needs to be consistent and ban everything—from oxygen to dexamethasone.' The tinkling of bells accompanies yaks hauling propane and other supplies to Advanced Base Camp. Photograph by Renan Ozturk, Nat Geo Image Collection
Before he became an advocate of xenon, Furtenbach had experimented with having clients sleep at home in tents with reduced oxygen and training with limited oxygen to help simulate the acclimatization process. That shortened the ascent time to three weeks.
Knowing this, Fries, the anaesthesiologist, approached Furtenbach back in 2019 with the idea of using xenon and its erythropoietin production ability to accelerate acclimatisation even further.
When confronted with limited oxygen at high altitude, the human body gradually releases erythropoietin after several weeks of acclimatisation, as a climber makes rounds up and down the mountain, slowly gaining altitude.
Fries, who spent 15 years researching different effects of xenon while working at Aachen University's hospital in Germany, theorized that a one-time low-dose administration of the gas could produce the same results in a matter of days. Fries also contends that xenon can prevent high-altitude sickness due, in part, to its positive effect on the blood vessels that connect the heart and lungs.
Furtenbach first tested xenon on himself in 2020 while climbing Argentina's 22,831-foot Aconcagua and, two years later, on Everest. Both times, he says, he felt strong and fast, and didn't experience any negative side effects.
Then he crafted a plan for including xenon in the expeditions offered by his self-titled company, Furtenbach Adventures, which facilitates climbs up Everest and other famous mountains. The decision to offer xenon to clients, he says, was done to make climbing safer.
'The fewer rotations you have to do on the mountain, the safer the expedition becomes,' he argues. (Furtenbach also thinks shorter trips could help curtail the large amounts of garbage long expeditions leave behind.)
For the first-ever xenon 'powered' expedition, he chose four British clients, who boasted a combination of high-altitude climbing experience and military training. After ten weeks of pre-acclimatisation at home, sleeping and training with limited oxygen, they received a low dose of xenon in a German hospital and two weeks later embarked from London on their five-day-long ascent. No immediate serious side effects from the xenon treatment were observed by Furtenbach or the members of the expedition.
The price of the climb was 150,000 euros a person. Furtenbach declined to specify how much xenon, an expensive gas, added to this total. Climbing rope is a ubiquitous tool amongst mountaineers, and learning how to safely build anchors and belay are essential skills. However, on some mountains, ropes may be pre-anchored and left in place for the entirety of the season to aid less experienced climbers. Left, the first Nepali female to climb Manaslu studies ice anchors in a climbing class. Right, a mountaineer descends to camp III during an attempt to summit Hkakabo Razi, said to be Southeast Asia's tallest mountain. Photograph by Aaron Huey, Nat Geo Image Collection (Top) (Left) and Photograph by Renan Ozturk, Nat Geo Image Collection (Bottom) (Right)
Not everyone with high-altitude expertise is convinced that xenon is the best way to quickly climb Everest.
Some experts argued that a one-week ascent might be possible without a miracle drug like xenon, if only the climbers would use a high enough flow of oxygen right from the bottom.
'If you have a big flow of oxygen, you don't need to work as hard to acclimatise. From an oxygen perspective, you're not going to the summit of Everest, but much lower,' says Mike Grocott, professor of anaesthesia and critical care at the University of Southampton in England and expert on the physiology of hypoxia.
This theory, too, was tested this May when Ukraine-born Andrew Ushakov stated that he climbed to the top of Everest in a little less than four days after leaving New York. To achieve this, he used supplemental oxygen and trained in low-oxygen conditions. A team from the Elite Exped company guided Ushakov to the top. He says he used oxygen as soon as he started his ascent from the base camp, starting with a flow of 0.5 liters per minute and slowly increasing it to three to four liters per minute, which he used on the summit day.
The xenon team, Furtenbach says, didn't start using oxygen until they reached 19,700 feet, continuing from there with a usual flow of 1 to 2 litres per minute. Higher flow was used only above 26,000 feet. This theoretically means xenon could indeed have some effect on the acclimatisation process, beyond supplemental oxygen.
Still, without peer-reviewed studies, it's hard to conclude that the xenon made a difference, warns Peter Hackett, a high-altitude researcher and professor at the University of Colorado Anschutz Medical Campus. 'My question is—why the big rush,' he says.
'These ascents reveal that Everest's challenge is now all about dealing with hypoxia and not really climbing.' For some climbers, no extra help wanted
Climbers who abstain from performance-boosting drugs and supplemental oxygen see xenon as just another departure from the purest, and thereby most elite, form of climbing.
The Piolet d'Or, the most coveted mountaineering award, perhaps best exemplifies the most prestigious climbing styles. The award currently doesn't consider ascents done with supplemental oxygen or fixed lines, giving the spotlight to imaginative and innovative new routes, doing more with less, and building on experience.
One of the winning teams of last year's Piolet d'Or, American climbers Matt Cornell, Jackson Marvell, and Alan Rousseau, spent seven days charting a new route up the steep north face of Jannu in Nepal. To pack lightly, they shared a single sleeping bag.
'Alpinism without the factor of the unknown is only the plain physical activity,' says Slovenian climbing legend Marko Prezelj, four-time winner of Piolet d'Or. 'If somebody prepares the mountain for you by putting in fixed lines and you climb together with 500 people, there is nothing unknown.' The Everest massif from Camp I on Pumori. Photograph by Cory Richards, Nat Geo Image Collection
Famous American alpinist Steve House, best known for his bold 'alpine style' first ascent on the Rupal face of Nanga Parbat in 2005, sees alpinism as a process of stripping away excesses to get closer to the experience.
'There is nothing inherently wrong with the ascents done with supplemental oxygen and xenon, but we need to understand these climbs as tourism, not alpinism,' says House.
And Mingma Gyalje Sherpa, the first Nepali to climb all 14 of the world's 8,000-meter peaks without supplemental oxygen and founder of the Nepal-based guiding company Imagine Nepal, says there should be a limit to what tour companies offer. He thinks that the traditional way of doing proper acclimatisation is more valuable.
'I would always suggest to clients to do at least one rotation on the mountain up to Camp 2, before the summit push, so they can understand their body at high altitude. We also don't take clients without previous experience,' he says.
But even if assisted climbs and medical aids become more common, Alpenglow Expeditions' Ballinger thinks there will always be an interest in unassisted alpine climbing.
'There are endless new route opportunities for alpinism in the Himalaya. And I don't think the fact that we have commercial guiding on a handful of routes on the world's most popular mountains gets in the way of the cutting-edge side of the sport,' says Ballinger.
Peter Hackett, the high-altitude researcher, is less optimistic.
'The improved access, safety, and success on Everest have led to a new 'generation' of high-altitude tourists with high ambition but little climbing experience, and more money than time,' he says. 'It's all about— how I can bag this summit and miss as little work as possible.'
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How human hibernation could revolutionize medicine and get us to Mars
Putting people into sleep mode is a sci-fi concept that's a lot closer to becoming real than you might think. Erin Belback is part of an ongoing human trial backed by NASA that aims to replicate the effects of hibernation in humans—a potential tool for overcoming some of the physiological problems of long-duration spaceflight. Scientists at the University of Pittsburgh plan to monitor her exhaled breath and body temperature to study her metabolic rate for their research. Photograph by Rebecca Hale, National Geographic Photographs by Corey Arnold The test subject had slipped into what physician Clifton Callaway describes as a 'twilight kind of sleep.' Eighteen hours after Callaway's team at the University of Pittsburgh's Applied Physiology Lab started the man on a sedative that suppressed his body's natural shivering response, his internal temperature had sunk from 98.6°F to 95°F. His heart rate and blood pressure had dropped. His metabolism—and, along with it, his need for food, oxygen, and carbon dioxide removal—had plunged 20 percent. Yet the subject could still rise from his bed, shuffle to the bathroom to empty his bladder, and, when hungry, ring a bell to ask for food or a drink—alleviating the need for a catheter or intravenous lines and ensuring he could still respond and react. The man was one of five exceedingly fit volunteers, ranging in age from 21 to 54, who quietly dozed in the semidarkness—pretend astronauts on a nine-month journey to Mars. NASA had tasked Callaway, an expert in cardiac care and induced hypothermia, with figuring out a simple way to put human beings into a state that mimics some of the key features of hibernation without the use of a ventilator or immobilizing drugs, and careful dosing of dexmedetomidine did the trick. His subject, Callaway says now, was woozy, dreamy, but still able to function in an emergency if required—'just like a bear.' Humans in hibernation mode are a classic staple of space travel in science fiction movies, whether it's HAL 9000 fatally unplugging a few of his passengers in 2001: A Space Odyssey or Chris Pratt waking up Jennifer Lawrence too soon because he's lonely in Passengers. But NASA has grand ambitions of sending astronauts to Mars, for real, as soon as the 2030s, and putting humans in hibernation mode, for real, could be the key to achieving it, which is why both NASA and the European Space Agency are supporting studies like Callaway's. A bearlike state of hibernation could, in theory, help astronauts snooze through the tedium of extended space travel and limit crewmate conflict. Their slowed metabolism could help reduce cargo: Missions would require less food and oxygen, and consequently less fuel. Space agency-funded research is even exploring whether slowing a person's metabolism weakens the health impact of harmful radiation. This would be an encouraging boost for the viability of extended travel through space, where radiation is as much as 200 times greater than on Earth. In fact, when it comes to achieving the dream of crew missions to Mars, says ESA's chief exploration scientist Angelique Van Ombergen, space radiation 'is a big showstopper.' Robert Foote, a volunteer in the NASA-supported trial in Pittsburgh, is monitored by scientists after being asleep for 20 hours. By achieving hibernation on demand, researchers could potentially unlock a wide range of medical benefits, including extending the time that doctors have to treat strokes and heart attacks. Photograph by Tim Betler, UPMC Scientists aren't studying hibernation just so we can ship astronauts ever deeper into space, though. Its physiological superpowers could save countless lives here on Earth, if we can unlock the secrets to the mysterious molecular-level changes that shift animals in and out of a state of hibernation, or 'torpor'—a miraculously reversible state of dormancy characterized by extreme lethargy, a lowered body temperature and metabolic rate, and a host of other remarkable changes. 'It's a well-established principle,' Callaway explains, 'that at low temperatures, like in hibernating animals, you tolerate lack of oxygen, lack of blood flow better and longer.' But why? Why don't bears' muscles atrophy while they sleep? How come their blood doesn't clot? And what triggers the process to begin with? In their hunt for answers, scientists are now inching closer to their most ambitious discovery yet: a central switch in the brains of hibernating animals that activates the various beneficial phenomena of hibernation, all at once. Mimicking the colder body temperature of bears during hibernation, for instance, could lessen the severity of 'reperfusion injuries,' the often devastating damage that occurs after cardiac arrest when blood flow is restored to the oxygen-deprived tissues of the body, setting off massive inflammation, oxidative stress, and cell death. It could also help extend the narrow window of time that doctors have to provide critical care during strokes and heart attacks. A clearer understanding of how hibernating bears preserve muscle mass and turn on and off insulin resistance could have other benefits: It might help us treat chronic obesity and diabetes in humans. ICU patients can lose more than 10 percent of their muscle mass in seven days. Could an induced state of hibernation stall or even stop the decline? Scientists are searching beyond bears for the answers because, of course, bears aren't the only animals that hibernate. A team at Colorado State University is investigating how the 13-lined ground squirrel can rapidly fatten and then switch off its appetite before hibernation for clues to combating obesity. UCLA researchers examining the genes of yellow--bellied marmots have recently found that 'epigenetic aging' is 'essentially stalled' during the seven to eight months they hibernate each year. Experts in Germany are exploring how bats maintain blood circulation at low temperatures, with an eye to human hibernation applications. And biologists at the University of Alaska Fairbanks are studying a squirrel that can drop its body temperature by 70 degrees and heart rate down to five beats per minute and survive eight months in subzero temperatures. Their goal is to develop a 'hibernation mimetic' drug that might safely allow clinicians to place humans into an immediate state of hibernation—without a long prep time, in a rural hospital lacking advanced equipment, or even in an ambulance racing through the streets. It would instantly dial down cellular metabolism, slow cell death, and catalyze a whole host of other biological processes associated with hibernation. (New bat discovery could help humans hibernate during space travel.) To decode hibernation's mysteries, biologists like Heiko Jansen are carefully studying the world's most notorious hibernators: bears. The 11 grizzlies housed at the Washington State University Bear Center are onetime 'trouble' bears from Yellowstone National Park and their offspring. Today they are sleeping for the benefit of science. The center's grizzlies are monitored in camera-equipped dens as they snooze through the late stages of their hibernation. For the five months they rest, their metabolism slows dramatically, reducing their need for food and oxygen. Callaway's twilight sleep experiment provides a glimpse into what might be possible for humans, but what happens in the lab and in the wild are clearly two different things. Bears don't need drugs to settle in for the winter—they have a natural 'torpor switch,' he says, which is flipped through some process that we don't fully understand. And though they're unruly, bears still offer a good comparison for our own potential: They're at least closer to us in size than a rodent, and, perhaps most critically, their temperature drop during deep sleep is well within the range of human survivability. One bright afternoon in late March, biologist Heiko Jansen stood outside a fenced-in pasture at the Washington State University Bear Research, Education, and Conservation Center in Pullman and watched as a shaggy 300-pound female grizzly bear named Kio struggled to eat a marshmallow. Other than a serious case of bedhead and the glacial pace of Kio's chewing, there were few visible clues that the dangerous, disheveled giant with the four-inch claws was undergoing a profound metamorphosis. Looking from the outside, little about Kio's metabolic process seems applicable to humans. Ten days earlier, she rose from her bed of straw and began to slowly work through a feast of bear kibble, apples, and elk bones and leg meat. It was her first meal in five months. Her salivary glands were still sluggish. Then she pooped out a 'fecal plug' composed of plants, dried feces, dead cells, and hair lodged in her lower intestine. Those three key activities—rise, eat, poop out the plug—seem to have helped flip a series of microscopic genetic switches inside her cells, catalyzing the slow-motion reversal of a host of bizarre biological cycles her body had entered into over the winter. Kio's metabolism, which had been operating at one-quarter its normal speed, kicked into gear, more than doubling by the time she was struggling with the marshmallow. Her core body temperature, hovering about 12 degrees below normal, began to rise. Two of her heart's four chambers, which had all but shut down for the winter, reopened for business. Her fat cells, for months miraculously resistant to insulin, the hormone that tells the body when to absorb sugar, started to respond to it again. Her appetite, absent for months, rumbled to life. When the grizzlies begin to stir, in March, they are awake but drowsy—their bodies beginning the process of reversing their metabolic slowdown. This bear, Adak, will be rewarded with honey and other treats after presenting his legs for a blood draw. Five months earlier, back in November, when Kio lay down and packed it in for the winter, she stopped eating, her gut entered 'stasis,' her saliva glands shut down, and she began living on her own body fat. Over the following months, she burned roughly 20 percent, or 70 pounds, of her body weight. To facilitate this, her body became resistant to insulin, a good thing for hibernators. Humans who become insulin resistant often develop diabetes—clearly a bad thing. Bears can switch that resistance on and off, depending on the season, without health consequences. If we could understand how, maybe we could figure out a way for humans to do it too? (Hibernating bears could hold a clue to treating diabetes.) The notion got a boost of confidence in 2018, when a Canadian group published the first complete grizzly bear DNA sequence. A year later, Jansen headed up a team that used a technique known as RNA sequencing to identify which genes are activated in bear muscle, fat, and liver tissue samples before, during, and after hibernation. They found seasonal changes in more than 10,000 of a grizzly's 30,723 genes. Now, in order to decode how bears switch insulin resistance on and off, Jansen has been extracting stem cells from blood samples collected from Pullman's bears at different times of year, methodically eliminating individual genes and then growing colonies of fat cells in petri dishes to see what happens. 'We're not saying that we'll find something that can reverse diabetes,' Jansen offers. 'But at least by looking at a model system, the cells that change their sensitivity, we can begin to develop some clues as to what's going on.' Kio's cardiac function might also yield insights that help treat human blood--clotting disorders. While Kio was hibernating, her heart rate slowed from 80 to 100 beats per minute to about 10. Normally this would cause her blood to clot into dangerous blockages and induce a stroke—'if that happened to us,' says Jansen, 'we'd be dead'—but hibernating bears also experience a remarkable drop in their blood-clotting platelets. It was Kio's ability to maintain muscle tone, however, that particularly transfixed some of her researchers. Unlike humans, who begin to lose muscle mass within a week of inactivity, Kio rose from her hibernation bed as fit as if she'd spent the winter chasing chipmunks. Up in Alaska, researchers Vadim Fedorov and Anna Goropashnaya are trying to unlock the mystery of how bears do this—and test the hypothesis that humans might be able to as well. The Russian-born husband-and-wife team specialize in evolutionary genetics at the University of Alaska's Institute of Arctic Biology (IAB), in Fairbanks. When they began analyzing gene expression patterns in tissue samples collected from captive black bears nearly 20 years ago, the results shocked them. Seeing as how bears stop eating and slow their metabolism during hibernation, Fedorov and Goropashnaya assumed the gene activity involved in building new muscles would be dialed down to preserve energy. Instead, the genes were just as active and even appeared to ramp up. 'We checked it several times,' says Goropashnaya. 'We couldn't believe it.' At the university's Institute for Arctic Biology, Anna Goropashnaya and Vadim Fedorov are investigating how muscle tissue of squirrels and bears (squirrel tissue is projected on their lab wall for this image) is preserved in hibernation when the animals don't eat and barely move. The findings were 'illogical' but somehow correct. Scores of genes known to be part of muscle protein biosynthesis were turned up in what appeared to be a coordinated—and metabolically costly—frenzy of activity. The two presented their first paper on the phenomenon in 2011. Now, with the aid of newer DNA sequencing technologies, they're able to study twice as many genes and with far more specificity, which is what led them to the mTOR pathway, a well-known cellular 'dial' that also plays a key role in controlling the rate of cell division. Typically, when mammals are starved of nutrients, their bodies dial mTOR down to suppress cell regeneration and steer energy to protect existing cells. But in the muscles of hibernating bears, the researchers confirmed what they'd first observed years earlier: mTOR increased instead. Fedorov and Goropashnaya were stumped. If hibernating bears are building new muscle, where are they getting the nutrients to make it? Researchers at the Universities of Wisconsin and Montreal have explored one possibility: microbes. Early findings in other hibernators indicate that instead of producing urine when hibernating, animals recycle the nitrogen in urea, and microbes in their guts could be ingesting and metabolizing it into amino acids, which make new muscles. If Fedorov and Goropashnaya can identify a single, extra-powerful 'upstream' gene responsible for switching on this muscle regeneration, it could have profound medical implications. The muscles of bedbound ICU patients wouldn't melt away within weeks, and astronauts could build muscles while resting. But what if all the disparate and remarkable processes of hibernation could be globally activated all at once—with a drug? To find out, scientists are looking deeper into the animal kingdom to unlock the secrets of the most extreme hibernator of all. (It's not just bears: These hibernating animals may surprise you.) The arctic ground squirrel, a diminutive rodent with gold-tinted fur, a button nose, and a tiny pair of Bugs Bunny-like front incisors, can drastically drop its body temperature and heart rate, slow to one breath per minute, and survive months in subzero conditions. The squirrels are also, for the most part, far easier to study than bears. An arctic ground squirrel remains in hibernation in a lab at the Institute of Arctic Biology at the University of Alaska Fairbanks. 'Until they open their eyes,' says Kelly Drew, the affable, silver-haired neuroscientist who directs the Center for Transformative Research in Metabolism at the IAB, after digging through a nest of cotton and wood shavings to pull out a frozen, furry snowball. 'Then they can bite.' In the early 2000s, Drew persuaded the U.S. military to fund a search for the brain chemicals that trigger hibernation in the squirrels. If she could identify those chemicals, she suggested, she could then test them on humans, in hopes of developing new ways to cool wounded soldiers on the battlefield. Drew's first breakthrough with the squirrels arrived in 2005 when an undergraduate research assistant chanced upon a paper from a Japanese lab while combing through scientific literature. The Japanese group had actually achieved the opposite of what Drew hoped to do. They'd found a drug that woke hibernating hamsters by blocking their brain cells' response to a specific chemical called adenosine. Drew assigned a graduate student to inject a synthetic version of adenosine, a drug called 6-Cyclohexyladenosine, or CHA, directly into the brains of her squirrels. Rather than blocking adenosine, which is how the caffeine in your coffee works its magic, CHA replicates its effects. When the graduate student dosed a squirrel's brain in the summer, outside of hibernation season, nothing happened. But when he repeated it closer to hibernation season, the CHA put the animal into such a deep state of torpor, the student initially thought he had killed it. 'He was super sad because that's a big deal,' Drew recalls. 'He takes the animal out for the vet to do the necropsy. The vet gets the tools out, he's going to start cutting open this dead animal, and it starts to move.' Her lab had done it. They'd found a way to put a squirrel in hibernation mode, like flipping a switch. Temporarily removed from its refrigerated hibernation den and settled on a bed of wood shavings, this arctic ground squirrel remained in a state of torpor for over an hour before beginning to stir. The squirrels survive their long hibernation by warming up for short periods every few weeks. On the opposite side of the world, at the University of Bologna in Italy, around the same time Drew's grad student stumbled on that Japanese paper about adenosine, another grad student named Domenico Tupone was charting a similar path. The focus of his laboratory research wasn't hibernation per se but a component of it: identifying the brain circuits that regulate body temperature during sleep. His team suspected that a small patch of neurons at the base of an ordinary rat's brain helped convey temperature-control signals to the periphery of the body. They temporarily immobilized those neurons with an injection, then placed the rat in a cold, dark cage. The experiment validated their hypothesis. As Tupone and his colleagues watched, the rat sank into a state of hypothermia so extreme it should have proved fatal. That's when things got weird. Six hours and four injections later, the hypothermic rat was still alive. And when the team finally removed it from its cage and warmed it up, the rat behaved, at least outwardly, as if nothing had happened. Afterward, as Tupone and his colleagues examined the brain waves picked up by a web of electrodes attached to the rodent's skull, scientist Matteo Cerri made an observation that altered the course of Tupone's future research. The peaks and valleys of the brain waves looked familiar. Cerri had seen the same patterns in hibernating animals. But there was one crucial difference. Unlike arctic ground squirrels, rats do not naturally hibernate. Tupone had to know: If a non-hibernating animal could be safely induced into hibernation, then maybe humans could do it too? In the years that followed, Tupone obsessed over scraps of paper in dimly lit bars, sketching out what a brain circuit capable of triggering hibernation in humans might look like. In bed, he tossed and turned, fantasizing about a 'revolutionary' IV-administered drug akin to Drew's 'hibernation mimetic' that paramedics could use to slow cell death on the way to the hospital. He became convinced that if it could be accomplished safely, inducing natural torpor in humans would upend basic science. The next step for both researchers, though—human trials—presented their stiffest obstacle yet. In order to administer Drew's 'hibernation mimetic' to ground squirrels, her team often had to perform invasive brain surgeries. For humans, the drug would need to be delivered via IV. The trouble is, adenosine receptors are present throughout the body, and activating them globally can trigger unwanted side effects, including cardiac arrest. After four more years of frustrating trial and error, Drew paired the drug with a compound that fixed the heart attack problem, and she's currently trying to solve the additional obstacle of fluctuating blood glucose levels, which in extreme cases can cause seizures in lab animals and even death. 'It works; it definitely cools them,' Drew says. 'We're just trying to tweak it so it's as safe as possible.' Clinicians have lots of devices to regulate temperature, 'but the human body typically fights it. By avoiding that cold defense response, which is what our hibernation mimetic does, then the clinician has the ability to dial in whatever temperature they want.' In minutes, not hours. Tupone, meanwhile, was working on parallel tracks at Portland's Oregon Health & Science University under Shaun Morrison, one of the world's experts on the brain circuits that control body temperature. Tupone's primary focus was on extending the map of temperature--related circuits into new parts of the brain, but in his spare time, he continued to hunt for the elusive hibernation switch. Around 2016, he stumbled upon a curious biological phenomenon that convinced him he was getting close. He and Morrison were attempting to confirm their map of the brain's thermoregulatory control system, in an experiment similar to the one in which the unexpected survival of those hypothermic Italian rats had blown his mind. This time, Tupone used a small knife to sever the bundle of nerves running to the rat's brain stem, cutting off the pathway that relays temperature--control signals down to the body's periphery. Once again, though, Tupone's results seemed to flip the expected rule of mammalian physiology. Rather than disabling the ability of the rat to respond to heat or cold, Tupone's incision somehow enhanced it. When Tupone wrapped the rat in a plastic blanket and ran hot water over it, its body began generating even more heat. When he used freezing cold water, the rat's brain seemed to allow its body temperature to fall even faster. An arctic ground squirrel emerges from a burrow in the foothills of Alaska's Brooks Range shortly after its eight-month hibernation. Each fall, Colorado State University scientists working at the nearby Toolik Field Station collar squirrels with devices to track body temperature data and light, which tells them if a squirrel is in or out of its burrow. In the spring, new squirrels are ear-tagged and weighed before their summer of foraging begins. The long-term study is revealing how climate change is affecting the biology of these important hibernators. Tupone and Morrison quickly concluded they had discovered something profound. The results suggested that a second, previously undiscovered brain circuit capable of modulating body temperature existed—one that facilitated the transition in and out of hibernation. They named the phenomenon 'thermoregulatory inversion' (TI). But where exactly was this circuit, and how could it be activated? After eight years of trial and error, Tupone and Morrison published a paper this past January announcing they'd found a small patch of neurons in the rat's hypothalamus—the ventromedial periventricular area (VMPeA)—that, when activated, not only seems to slow metabolism, lower body temperature, and induce brain waves and cardiac patterns unique to hibernation but also sets in motion phenomena that flip the body's normal temperature-control system on its head, facilitating the transition into and out of the torpor state. They'd found it: the elusive 'torpor switch.' Tupone believes the switch is connected to an incomplete version of the hibernation circuitry that still exists in many animals. To disable it, he hypothesizes, evolution did the most efficient thing. It simply removed the connection between the circuitry and the switch that would flip it on automatically. 'It is like you have all the cables inside your walls to turn on a light,' he says, but you've removed the connection to the switch that controls that light. 'We think humans have all the circuitry.' Our switch, he believes, just isn't connected anymore. To back up his findings, Tupone is now collaborating with Kelly Drew's lab to find the analogous circuitry—and the switch—in arctic ground squirrels. And he's laying the groundwork for a drug of his own that can flip the switch in his rats without invasive brain surgery. Each advance, though, generates more mysteries. To flip their switch on and off in the study they published in January, Tupone and Morrison had to use invasive brain surgery and manually apply a drug to the general area where it was located. Even that infinitesimally small patch of the brain still contained millions of neurons, including an entire neighborhood of unrelated neurons surrounding it. To find a drug specific enough to give to humans without immense side effects, Tupone will need to identify the precise neurons around the switch and design a drug that will target only those involved in hibernation. That's just the tip of the iceberg, though. To suppress the shivering response in humans, anesthesiologists typically administer muscle relaxants or paralyzing drugs, which suppress breathing, so doctors have to intubate patients … which requires putting them into a medically induced coma. This is why induced hypothermia is not available outside hospitals. It's also not currently an option for stroke patients, because of the dangerous drop in blood pressure that often occurs during the gap between administering anesthesia and intubating a patient, which can deprive the brain of even more oxygen at a moment when dangerous blockages are already suffocating its cells. Rats don't hibernate. But what if they could? Neurologist Domenico Tupone and fellow researchers from the University of Oregon say they've identified a 'torpor switch' in rat brain neurons (projected on the wall) that can be activated to send the rodents into a deep state of hibernation. Identifying this circuitry in non-hibernators could be a breakthrough in the human hibernation effort. 'It can actually worsen a stroke,' says researcher Cal-laway, from the University of Pittsburgh. 'But boy, it sure would be nice to lower your body temperature and let your brain tolerate the stroke longer until I can get you to the cath lab and take that blood clot out.' As an emergency physician, Callaway understands better than most the potential applications for humans, as well as the challenges presented by making the leap from bears and squirrels to humans. He's been researching and refining the techniques used to induce hypothermia in cardiac and brain-injured patients since the 1990s, and he's also a former chair of the American Heart Association's Emergency Cardiovascular Care Committee, which is why NASA awarded him a grant through the Translational Research Institute for Space Health to explore whether his techniques can be applied to the metabolic needs of astronauts. So far, there are problems. The drop in blood pressure and heart rate in his five healthy volunteers was so extreme that those with cardiovascular or other medical conditions might not be able to tolerate it. And within days, all five of the 'pretend astronauts' had developed a tolerance to his sedative, suggesting, among other things, that its effectiveness would fade over time. Those are solvable problems, Callaway says. 'This is just the first step' in a process that he believes will take 10 to 15 years—a mere nap for Rip Van Winkle. 'There's a lot of science to be done,' he says. But he's excited by the progress: 'I don't think it's pie-in-the-sky anymore.' To keep the pretend astronauts inspired during the human trial, Callaway's team had plastered the walls of their lab with posters: a satellite floating in space above the swirling blues and whites of Earth; the cratered, gleaming surface of a moonlike planet; the rainbow-hued burst of starlight, radiating from a distant galaxy. For now, such destinations are accessible only in our dreams. But someday in the not too distant future, a real astronaut might awaken from a hibernation-like slumber to gaze on the real thing.
Yahoo
2 days ago
- Yahoo
Merck's $2 Billion Bet: The Tiny Biotech That Could Save Its Neurology Pipeline
Merck KGaA (NYSE:MRK) is going back on offense in neurologyand it's betting big. The German drugmaker just announced a collaboration with Skyhawk Therapeutics that could top $2 billion, aimed at developing RNA-targeting small molecules for hard-to-treat neurological diseases. Under the deal, Skyhawk will lead discovery and preclinical development using its proprietary RNA splicing tech, while Merck steps in if the science clears early hurdles. Though financial terms weren't disclosed, the structure includes upfront and milestone payments, plus royalties tied to future sales. Warning! GuruFocus has detected 2 Warning Sign with MRK. This isn't a pivot. It's a rebuild. After two major clinical failures rocked its pipeline and with its blockbuster multiple sclerosis drug Mavenclad losing exclusivity starting in 2026, Merck is under pressure to restock its innovation shelf. CEO Belen Garijo is tightening focus on external innovationand fast. That includes this Skyhawk deal, and the recently closed acquisition of SpringWorks Therapeutics, which is expected to start contributing to Merck's healthcare revenue in the second half of this year. Behind the scenes, this deal speaks volumes about where Merck thinks the next frontier lies. Amy Kao, who heads neuroscience and immunology research at Merck, called RNA splicing modulation an exciting frontierand that might be understating it. The company is betting that Skyhawk's tech could unlock new treatments where traditional approaches have failed. If even one program makes it through to commercialization, it could mark a turning point in Merck's quest to reignite long-term growth in its pharma arm. This article first appeared on GuruFocus. Sign in to access your portfolio
National Geographic
2 days ago
- National Geographic
What is the Jurassic period and why did it end?
The heyday of dinosaurs, the Jurassic era saw Earth's climate change from hot and dry to humid and subtropical. The Jurassic period was characterized by a warm, wet climate that gave rise to lush vegetation and abundant life. Many new dinosaurs emerged—in great numbers. Above, Dimorphodon reptiles fly over a herd of Mamenchisaurus dinosaurs coming down to a river for a drink. Illustration by CoreyFord, Getty Images By National Geographic Staff Thanks to this rich record, we know that the Jurassic was the height of dinosaurs roaming a tropical Earth filled with ferns, flowering plants, and conifers. It was also a time when sea monsters, sharks, and blood-red plankton filled inland seas borne of crumbling landmasses. Here's what the Jurassic period was really like. ('Jaw-dropping' fossil reveals epic prehistoric battle) Environmental conditions during the Jurassic At the start of the Jurassic era, the breakup of the supercontinent Pangaea continued and accelerated. Laurasia, the northern hemisphere, broke up into North America and Eurasia. Gondwana, the southern half, began to break up by the middle Jurassic. (In 250 million years, this may be the only continent on Earth) The eastern portion—Antarctica, Madagascar, India, and Australia—split from the western half, Africa and South America. New oceans flooded the spaces in between. Mountains rose on the seafloor, pushing sea levels higher and onto the continents. All this water gave the previously hot and dry climate a humid and drippy subtropical feel. Dry deserts slowly took on a greener hue. Palm tree-like cycads were abundant, as were conifers such as araucaria and pines. ('Living fossil' cycad plants are actually evolution's comeback kings) Ginkgoes carpeted the mid- to high northern latitudes, and podocarps, a type of conifer, were particularly successful south of the Equator. Tree ferns were also present. (Huge fossil is oldest giant flowering tree in North America) The oceans, especially the newly formed shallow interior seas, teemed with diverse and abundant life. At the top of the food chain were the long-necked and paddle-finned plesiosaurs, giant marine crocodiles, sharks, and rays. Fishlike ichthyosaurs, squidlike cephalopods, and coil-shelled ammonites were abundant. Coral reefs grew in the warm waters, and sponges, snails, and mollusks flourished. Microscopic, free-floating plankton proliferated and may have turned parts of the ocean red. (See the microscopic world of plankton in stunning detail) Dinosaurs flourished during the Jurassic period. Species such as Harpactognathus, Camarasaurus, Ceratosaurus, Allosaurus, Camptosaurus, Marshosaurus, and Megalneusaurus (illustrated above) quickly dominated the world. Illustration by Sergey Krasovskiy,Jurassic period dinosaurs On land, dinosaurs were making their mark in a big way—literally. The plant-eating sauropod Brachiosaurus stood up to 52 feet (16 meters) tall, stretched some 85 feet (26 meters) long, and weighed more than 80 tons. (How the world's deadliest mass extinction actually helped the rise of dinosaurs) Diplodocus, another sauropod, was 90 feet (27 meters) long. These dinosaurs' sheer size may have deterred attack from Allosaurus, a bulky, meat-eating dinosaur that walked on two powerful legs. This story originally published on January 6, 2017. It was updated on August 18, 2025.
