Chasing Ghosts: Unlocking the Mysteries of Human Hibernation
Mount Rokkō towers over the Japanese city of Kobe, a landscape of rolling hills complete with hiking trails and an unparalleled view of Osaka Bay. Every year, the 3,000-foot-high peak becomes awash with the red, yellow and orange leaves of fall, making it a popular destination for barbecues and youthful revelry.
In October 2006, Rokkō provided the perfect place for Mitsutaka Uchikoshi, a 35-year-old civil servant, to go picnicking with a group of friends. After a day spent sharing food and stories near the peak, Uchikoshi's friends decided to take the cable car back to Rokkō's base and head home. Uchikoshi chose to hike down one of the mountain paths alone.
Then he disappeared.
On his way down, Uchikoshi lost his footing, causing him to slip, knock his head and break his pelvis. Unable to move or call for help, he lay wounded on the side of the mountain. At night the autumn cold, dropping as low as 50 degrees Fahrenheit, crept into his bones. He passed out.
After 24 days, he was found by a passing climber and transferred to Kobe City Medical Center General Hospital. He was extremely hypothermic and cold to the touch. Many of his organs were failing. According to news reports at the time, Uchikoshi's doctors reasoned he had fallen into a state "similar to hibernation," just like a groundhog might.
When I first heard the story, I quickly became fascinated by it -- for two reasons. First, it was a tale of superhuman survival. Uchikoshi had overcome broken bones, freezing cold and extreme levels of hunger that should have killed him. Not only did he survive, he was discharged from hospital after 50 days with no lasting injuries. If his doctors were right, something must have changed in Uchikoshi's brain, enabling his body to enter an unheard-of period of stasis. But what exactly?
Second was the story itself. Doctors at Kobe Hospital were incredulous that Uchikoshi had survived. The spate of press the case received suggested other physicians, outside of Kobe, were skeptical this was really hibernation at all. Some deemed the feat physiologically impossible. Once Uchikoshi was released from the hospital, the press and scientists seemed to forget about his case. There were no reports in the scientific literature as to what, exactly, had kept him alive and no explanation for his extraordinary persistence on the peak. Yet his tale remains one of the most commonly cited examples of a latent ability for humans to hibernate.
What really happened to Mitsutaka Uchikoshi on that mountain in 2006? I began trawling the web in 2019, searching for leads on his whereabouts. I fired off emails to journalists who had been at the press conference in 2006. I asked Japanese researchers I knew, from the nation's space agency and other facilities, to see if they could track him down or if they could find the doctor who fronted the presser.
To understand his ordeal on the mountain, I would need to investigate how scientists are using extreme cold to induce a state of suspended animation in trauma patients. I would need to learn what spaceflight companies think about hibernation during interplanetary voyages, beyond the orbit of the moon and Mars, and explore how neuroscientists are unraveling the chemical mysteries inside the brain to activate hibernation-like states in other mammals. And lastly, I would need to try to find Uchikoshi.
Uchikoshi's hibernation had become a holy grail, but it seemed like he'd become a ghost. Chasing that ghost first led me to zombies.
In 1999, a handful of researchers from the Safar Center for Resuscitation Research at the University of Pittsburgh sent a pack of hunting dogs to the afterlife.
Then they brought them back.
The "zombie dogs," as they were christened by a New York Times headline in 2005, demonstrated that rapid cooling of the circulatory system could send the canines into a state of suspended animation.
In the Safar Center's procedure, the dogs' blood was drained from their bodies and slowly replaced with a cold, saline fluid providing basic nutrients and oxygen. Without blood, the dogs' hearts stopped and their brains went quiet. Clinically dead. Researchers removed the cold saline fluid and returned the warm blood 60 minutes later. The dogs, after a jolting electric shock, were revived. The majority of the canines didn't suffer any brain damage.
It's one of the more profound experiments studying "therapeutic hypothermia," a practice that's become common in hospitals around the world for a handful of conditions, such as heart attacks and brain injuries caused by oxygen deprivation. If we think of the brain like a computer, therapeutic hypothermia enables it to be put in standby, keeping it powered but preventing it from completely shutting down. This gives doctors time to repair and reboot patients.
The work on the zombie dogs opened up the possibility that trauma patients, who quickly lose gallons of blood due to a stab wound or gunshot injury, could avoid death if their bodies were efficiently cooled.
The science of therapeutic hypothermia is well understood. Our cells use oxygen to create energy. Under normal circumstances, the heart pumps it around our body. In trauma patients, the loss of blood leads to cardiac arrest and cells quickly become starved and die. Cooling the body down by a few degrees causes cells to slow down, so they require less energy and less oxygen.
In 2016, in an FDA-approved clinical trial, a team of surgeons at the University of Maryland School of Medicine, led by Dr. Samuel Tisherman, began investigating how the procedure might help these patients survive. It is hoped that the process, known as Emergency Preservation and Resuscitation, will improve the odds of survival for trauma patients without doing any damage to their brains.
Scientists have shown that the procedure works in pigs, but Tisherman's human trial has been difficult to get off the ground. It requires patients to arrive at the emergency department when specialized doctors, like Tisherman, are in the building and ready to perform the procedure. First floated over a decade ago, it only just reached a significant milestone, enrolling the first human patient and placing that person temporarily in "suspended animation" in November 2019. It's expected that 10 people will be enrolled by the trial's completion.
The full results of the trial are still pending and have been delayed twice, with the pandemic throwing an extra wrench in the works. It's now expected to be complete in December 2023, according to its listing on the US clinical trials database.
In Tisherman's trial lies a potential answer to Uchikoshi's good fortune on the mountain. Had hypothermia contributed to his survival? Possibly. If Uchikoshi experienced a form of hypothermia that forced his brain to switch to standby mode, it could have slowed his metabolism and lowered the amount of energy he needed to get from food and water.
The clinical trial is trying to keep patients in a state of suspended animation for only minutes or, at most, an hour or so — long enough for doctors to repair traumatic injuries. As Tisherman told New Scientist in 2019, "I want to make clear that we're not trying to send people off to Saturn."
But Uchikoshi's long period of inactivity and subsequent recovery suggests such a future might be possible.
The moon or Mars
At its closest, Saturn lies around 750 million miles from the Earth. A crewed journey to the the solar system's ringed jewel could take upwards of five years and would require huge resources to house, feed and entertain astronauts. That is, unless you can drop travelers into a hibernation-like state.
Short spaceflights pose some risks to astronauts, but decades in the future, humans could spend months or years venturing farther into space, beyond the moon and Mars, where such risks are greatly amplified.
The physiological perils of long-duration spaceflight are many. Cosmic radiation constantly crashes into the body, intense isolation plays havoc on the mind, and microgravity causes muscles and bones to waste away.
"From animal research, it's known that hibernation can minimize and positively affect all three," said Jennifer Ngo-Anh, a scientist with the European Space Agency.
Hibernating animals, like bats and hedgehogs, don't suffer from degeneration of muscles or bones. Other animals, like bears, enter a hibernation-like state known as torpor. Torpor is classically defined as a state of involuntary hibernation that organisms enter to survive harsh environments devoid of energy sources, like food and water. It's basically hibernation lite.
If we can unravel why animals do this and understand how to induce torpor in humans, we might prevent some of the worst problems associated with leaving Earth for long periods.
"This is game-changing technology," said John Bradford, president and CTO of SpaceWorks Enterprises, an engineering company based in Atlanta. Bradford, who I spoke to in 2019, believes the ability to cool humans and place them in suspended animation will allow us to "really achieve something in space."
Bradford and his team have worked on human hibernation since 2012 and received second round funding in 2016 via NASA through the agency's Innovative Advanced Concepts program. Their idea is to induce and regulate torpor in astronauts using the principles of therapeutic hypothermia.
"Therapeutic hypothermia is nowhere near as extreme as what we see in the movies," said Bradford. "You always see somebody go into suspended animation for 100 years or something. We don't need that."
Instead, SpaceWorks has proposed a method it's dubbed synthetic torpor. A theoretical mission to Mars would see astronauts go under for up to 14 days, only to be woken for an active period that lasts three or four days. "By breaking it up, the challenges are reduced significantly," Bradford said. The hibernation-in-shifts model means there would always be a member of the crew awake through the 200-plus day journey, addressing safety concerns or any emergencies that might occur.
It could also help closer to home. Bradford said synthetic torpor could be key to establishing colonies on the moon, should we ever go down that path. You don't need it to take small crews to the lunar surface on the three-day journey, but if you were sending entire communities, the infrastructure problems become much more complex. "If you were wanting to send a thousand people, three days isn't easy," he said.
Torpor may be the answer.
"We can put them in this low metabolic state here on Earth, launch the ship, it lands on the moon [and you] wake everybody up a couple days later," Bradford said.
It sounds simple enough, but our understanding of how hibernation works is far too rudimentary to achieve what Bradford proposes anytime soon. Humans just aren't supposed to hibernate: We're not built that way. Uchikoshi's survival on the Japanese mountain has always been an outlier, not the norm, though it does potentially show there are no lingering effects of a state like synthetic torpor.
And recent research suggests the key to inducing such a state might be tweaking a specialized cluster of cells, tucked into the temperature-regulating zone of the brain.
Questions about Q neurons
Mice aren't natural hibernators, but they're capable of dramatically slowing down their metabolism when food is scarce. They, too, enter torpor.
Researchers have been able to take advantage of this physiological quirk and induce torpor in lab rodents by restricting their food intake or reducing the temperature of their enclosures. The interventions give researchers a chance to probe the mechanisms behind these states, particularly regarding changes occurring in the brain.
Two studies, published in the journal Nature in 2020, examined how clusters of brain cells, or neurons, are tied to torpor and hibernation-like states in rodents. Both teams focused on a region of the brain known as the hypothalamus, a bundling of cells responsible for temperature regulation, and found distinct populations they could link to torpor.
One team, led by Takeshi Sakurai, a researcher at the University of Tsukuba in Japan, focused on a set of brain cells involved in the brain's complicated temperature circuitry. The team dubbed this group of cells Q neurons. Using genetically engineered mice, Sakurai and team were able to take control of these cells, injecting a drug into the mice that activates the cells, like flicking a switch.
Turning Q neurons on dropped the body temperature of the mice from 96.8 degrees Fahrenheit (36 degrees C) to as low as 71.6 degrees Fahrenheit (22 degrees C). Heart rate and respiration slowed. Mice were maintained in this hibernation-like state for two days -- sometimes even longer. Once the Q neurons were switched off, Sakurai's team examined the organs of the mice and found no obvious changes to brains, hearts, livers or kidneys.
Hypothermia would typically cause shivering and eventually loss of consciousness, but Sakurai believes the Q neuron-induced hypothermia, or QIH, didn't cause the mice to "feel cold." Rather, it "shifts the state of the body," he said. These brain cells signal other organ systems and hormones to make adjustments, tricking the body into saving energy by lowering metabolic needs.
"For a mouse under QIH, a body temperature of 22 degrees Celsius is a comfortable state," Sakurai said.
Rodents don't naturally hibernate, so unlocking this potential is a leap forward in understanding the brain's control system. Sakurai said the team will potentially study golden hamsters, which naturally enter hibernation, to see if manipulating Q neurons results in the same effects they've seen in mice.
Genshiro Sunagawa, a co-author on the paper from Japan's Riken research institute, said the team wants to look at individual tissues and organs during the Q neuron-induced hibernation state and understand how exactly their metabolism is slowed. This could lead to targeted ways to put individual organs into suspended animation. "This will surely impact regenerative medicine or transplantation medicine," he said.
The research also highlights potential mechanisms that could have led to hiker Uchikoshi's hibernation-like state. It's impossible to know how his brain was affected during his time on the mountain, but if his Q neurons had been firing, perhaps they'd tricked his body into thinking 50 degrees Fahrenheit wasn't really life-threatening, but comfortable.
However, Q neurons are likely only a part of the equation. The other study, led by Harvard neurobiologist Sinisa Hrvatin, looked at neurons in a different part of the hypothalamus. Activation of these cells, dubbed avMLPA neurons, induced torpor in mice. Basically, the two studies show that stimulating similar areas of the brain is enough to drop the rodents into a deep sleep.
But the brain is a tangled circuit blasting out electrical impulses nonstop. Just discovering clusters of cells that seem to alter the physiological state of the body isn't enough to reliably activate hibernation in humans.
"A lot more research is needed to understand how animals enter, regulate and survive these states and whether they can be safely induced in other mammals — including humans," said Hrvatin.
I asked both Sunagawa and Sakurai whether they were familiar with the tale of Mitsutaka Uchikoshi. They both knew of the story but had little extra information. The ghost of Mount Rokkō remained elusive. But late in the evening on a Friday night in October 2021, three years after I started searching for Uchikoshi, my inbox dinged with the sound of a new email.
The ghost of Mount Rokkō
The message came from Keiko Kobayashi, international affairs coordinator at the Kobe Biomedical Innovation Cluster, home to the hospital where Uchikoshi was treated after his rescue. She'd found two doctors who had administered treatment to Uchikoshi in 2006.
The main attending doctor on the case was Takeya Minami, a cardiovascular expert. I quickly learned that he, too, had been chasing the ghost of Uchikoshi for more than a decade.
When I interviewed him in December 2021, he said the incident has had "quite a big impact on his career." Ever since Uchikoshi was wheeled into the hospital 16 years ago, he's been trying to unravel what happened on Mount Rokkō. He presented the case at conferences, speaking with experts in hormones, metabolism, body temperature control and neuroscience to try to understand how Uchikoshi survived.
"This is important for the field of medicine to unravel this particular case," Minami told me, via Kobayashi.
What we know is this: When Uchikoshi arrived at the hospital, he was sent to the emergency department, where physicians including Minami, and another doctor, Daisuke Mizu, attended to him. A rectal thermometer reading showed Uchikoshi's core temperature was just 72.3 degrees Fahrenheit. That is 25 degrees colder than normal. "We were surprised that hypothermia could get that bad," Mizu said.
Minami and Mizu helped to rewarm Uchikoshi's body by bathing him in warm water, but almost immediately he went into cardiac arrest. This is common for hypothermic patients because the cold results in a dysregulated heartbeat. The team performed CPR for over two hours, as his body slowly rewarmed and, eventually, his heart began beating on its own again.
Further examination confirmed Uchikoshi had been immobilized — there was very little chance he'd been able to move around the mountain. X-rays showed his hip bone was broken and had started healing by the time he was rescued. His stomach was entirely empty. He had tick bites on his feet and his skin was sunburned, particularly where he'd been holding his hand up to shield himself from the light before falling unconscious.
Minami said he was "simply amazed" Uchikoshi survived and had no lingering health problems. But the case is so outside of the norm that it still puzzles him. He interrogated the physiological data, studied weather patterns on the mountain and used computer simulations to reconstruct what was happening in Uchikoshi's body during the ordeal.
With all he's learned, Minami suggests the stranded patient's core body temperature likely crashed in the days following his disappearance and his fall. As he fell unconscious, the brain took over, slowing down his base metabolic rate to a point where it was able to preserve energy and keep his organs functioning. After discussing the case with colleagues for years, Minami has settled on a somewhat ambiguous answer.
"I could not say that this case was definitely due to the hibernation," he said, but he does refer to it as a "torpor-like" condition.
A dream in deep sleep
Occasional tales of superhuman survival continue to surprise scientists.
Six years after Uchikoshi walked out of Kobe Hospital, another extraordinary case came to light: A 44-year-old Swedish man spent two months stranded inside his car during a blizzard, under a thick layer of snow, with temperatures outside reaching -22 degrees Fahrenheit (-30 degrees C). He told police officers he'd been without food but had eaten snow to survive.
His doctors were just as stunned as those from Kobe hospital and suggested the man's body may have adapted to the slightly cooler temperatures inside the car, dropping well below normal in an effort to conserve energy. Hibernation, by any other name.
The common thread, from zombie dogs to Swedish survivors, is the body's ability to respond to changes in temperature. A chilly winter evening inspires the subconscious responses we're aware of -- goosebumps and shivering -- but it seems humans retain some capacity to go even further, dropping into a state of suspended animation without lasting negative effects under the most extreme conditions.
When I interviewed Minami in December 2021, he asked whether I'd been able to locate Uchikoshi. I told him I hadn't. He, too, had tried and failed, noting that Uchikoshi had routinely visited Kobe Hospital in the two years after his accident. From 2008 onward, no one knows what happened to him. This was, I felt, the last chance to find him. He'd proved elusive again.
I'd started the search with a question: What really happened to Uchikoshi on the mountain in 2006? I reached the end of the journey without an answer. There's no way of knowing exactly how his brain and body reacted while unconscious for more than three weeks. There's probably no chance of learning how he escaped his fate. All we know for certain is that he survived.
But in searching for him, it became clear the dream of human hibernation is alive and well. In a few decades, feats like Uchikoshi's may not just be short, involuntary naps inspired by a base biological drive to survive. Instead, we might be deliberately cooled for hours after a traumatic accident, buying doctors time to heal us, or dropped into months-long bouts of metabolic stasis to venture past the orbit of Mars and beyond.
Perhaps, in those moments, we'll finally understand what happened to Mitsutaka Uchikoshi.