What Can Hibernation Do for Humans?
Survive massive trauma, lose weight in your sleep, maintain muscle strength in space — all thanks to tricks from sleeping squirrels.
For Matt Andrews, a path to better human health starts inside a tiny sleeping animal. Andrews is a molecular biologist who became interested in how animals hibernate in the 1990s, when gene sequencing technology started to let researchers understand on a deeper level how animals survived long, cold winters in suspended animation.
Now, he thinks hibernation science could be an answer to some persistent serious human health problems, including stroke, obesity, heart attacks, and even the muscle loss that afflicts astronauts living in zero-gravity. That’s because hibernating creatures like the thirteen-lined ground squirrel he studies know to stop eating when the time is right, survive the winter by moving fat deposits around their bodies while they sleep, and manage low blood oxygen that would kill most mammals. After all that, they pop right out of their limbo in the spring, immediately able to elude predators.
By taking tips from hibernators, Andrews and his colleagues hope to change the prognosis for hemorrhagic shock, which occurs when the body begins to shut down due to massive blood loss. A decade ago, he teamed up with Greg Beilman, a trauma surgeon who had been a military reservist for 25 years. “I’ve done several overseas deployments, so I had a burning interest in how to better take care of our kids who are volunteering to serve overseas,” says Beilman, now a surgeon and researcher at University of Minnesota. “I’ve seen people who have bled to death before making it into the hospital. And I’ve seen lots of people who suffer side effects of the delay of getting to a place where they can stop the bleeding.”
Saving the life of a soldier who is bleeding profusely becomes a race against the clock — after the so-called “golden hour” following the injury, the wounded person’s chance of survival drops off precipitously. Andrews suspected that treatments based on hibernation biology could allow medics to extend that golden hour, buying time before a person’s tissues and brain cells start dying due to lack of oxygen and other critical components in blood.
“Hibernators survive extremes of low blood flow and low oxygen to blood tissues,” says Andrews. They can depress their metabolic rate, which protects the heart. He noticed that thirteen-lined ground squirrels (also known as striped gophers) produce higher levels of a natural compound called D-beta hydroxybutyrate (BHB) while hibernating and also have increased levels of melatonin during short mid-hibernation awakenings. The two compounds, he realized, play an important role in allowing the squirrel’s blood flow and metabolism to naturally ebb without harming its organs.
The formula could be used not just on the battlefield, but also for traffic accident victims or other trauma patients to help keep their organs alive.
Would these compounds also help organs and tissues survive hemorrhagic shock? Andrews, Beilman, and another colleague found that injections of that mix, when given to animals with severe blood loss, helped them survive nearly four times longer. They patented their formula, beta-hydroxybutyrate and melatonin — commonly referred to as BHB/M — in 2007.
Next year, the team plans to launch a trial in humans — at first, simply in healthy volunteers to make sure the compound is safe. Eventually, Beilman imagines BHB/M could be used not just on the battlefield, but also for traffic accident victims or other trauma patients to help keep their organs alive until they reach a hospital.
From cold animals to warm bodies
For thirteen-lined ground squirrels, which live in North American pastures and prairies, the fall is a busy time. The half-pound creatures pork up in anticipation of colder months. A squirrel winters in an underground burrow, curled up in a ball, with its body temperature hovering just above freezing. Its heart slows from the typical 300 beats per minute to between 3 and 10 beats per minute. During these months, it will lose a third of its body weight.
And yet as soon as the thaw hits, these rodents seem to miraculously snap out of their stupor, immediately able to avoid the claws and beaks of owls and eagles. The mystery of how they and other creatures like bats, snakes, frogs, and worms are able to do this has fascinated scientists like Andrews since the early 19th century.
Andrews is still exploring the basic biology of these animals, but he has also been quick to see the medical applications of what he learns. Andrews moved his lab to Oregon State University in 2016, teaming up with Adam Higgins, a bioengineer with expertise in cooling cells and tissues. Higgins knew a bit about how biology works in cold conditions and a lot about transplanting organs, but he didn’t know what Andrews knew about the surprising strategies of hibernating animals.
They both realized that hibernation biology could also be used to reduce the number of people who die each year while waiting for an organ transplant. As of April 2018, there are more than 114,000 candidates for transplant on the U.S. national waiting list, but there were only 34,800 transplants performed in 2017.
One problem is that many of these precious organs don’t last very long. Live kidneys have a shelf life of 24 to 36 hours, but hearts and lungs last only four to six hours outside the body. Many otherwise-suitable organs die before they can be transported and transplanted into a recipient.
These limitations mean that in non-planned donations — for example, when a kidney or heart becomes available after a fatal traffic accident — doctors don’t have time to first prime the recipient to accept the organ. As a result, the recipient may have to take immunosuppressive drugs for a long time afterwards.
Suspended animation also seems to elongate lives: Animals that hibernate live longer, on average, than similar species that don’t hibernate.
Andrews and Higgins think it’s possible to extend the shelf life by pre-conditioning the organs inside the donor before surgery. That might add a week or more of viability to an organ.
For now, Andrews and Higgins are experimenting on rats, treating them with a modified version of the BHB/M hibernation solution. The hope is that it can switch the metabolism of the donor organ, slowing it down and protecting it against damage.
The ultimate vision is that a person who is planning to donate an organ (or someone who is brain dead and previously agreed to donate) can be pre-conditioned with the solution, which in rats takes about an hour. “Now when you harvest the organs you will have a greater shelf life because you preserved them while they were still in the donor,” says Andrews.
Once the organs are removed from a donor’s body, researchers still need better ways to cool them, store them, and warm them back up. Hibernation strategies can help drive advances in those areas too, says Andrews. The team is planning experiments in these techniques with larger animals like pigs.
Staying fit en route to Mars
Hibernation biology has potential applications that go beyond medicine to general health and wellbeing, says Andrews. To cope with the winter, the squirrels build up reserves of brown adipose fat, which he calls nature’s fat-burning machine. What we usually think of fat is white fat, which stores calories for use later. Brown fat instead burns calories incredibly fast to generate heat.
In a 2013 study, Andrews and colleagues generated a transcriptome — a collection of all the gene readouts in a tissue — for squirrel brown fat over the course of a year.
During hibernation, the animals wake up every 10 days or so and their metabolism kicks in for a while before they go back to sleep. They use brown fat to warm themselves up from near-freezing temperatures during those times. Through other protein expression work, Andrews found that the animals move fat stores to their hearts and turn on special genes to make the fat burnable. “They selectively switch their body chemistry to burn fat instead of sugar,” he says.
Humans spend a third of their lives in a state similar to hibernation: sleep. If we could acquire the biology of hibernators, Andrews predicts, we could take a pill that revs up fat-burning before bedtime, and wake up a pound lighter.
Kelly Drew, a biochemist at the University of Alaska Fairbanks who studies arctic squirrels, says Andrews’ research was the first to pinpoint a molecular mechanism that contributes to the seasonal shift from carbohydrate to lipid metabolism in hibernation. “He has applied this knowledge to develop a novel and effective treatment for hemorrhagic shock,” she says. “His innovative research illustrates how study of hibernation can lead to novel solutions for human medicine.”
If we could acquire the biology of hibernators, Andrews predicts, we could take a pill that revs up fat-burning before bedtime, and wake up a pound lighter
Hibernation also seems to somehow protect muscles: Even though they don’t move much at all for five months, the squirrels can sprint away very soon after waking up. By contrast, people on bedrest or on an extended trip in space lose so much muscle strength that they may have trouble walking afterward. Someone on an 18-month trip to Mars would arrive with severe muscle atrophy, says Andrews: “You’d be all wobbly.”
For people who have trouble saying no to another plate of pasta even when stuffed, hibernating squirrels have another physiological trick. They gorge themselves with seeds and plants late in the summer, but when they reach a certain size, they stop. “They say: ‘I’m full, I’ve eaten enough,’ and they eat nothing more,” Andrews says. “Something in the brain is enforcing that satiety signal.” Decoding that signal and applying it to humans could help people stop eating when they’re full.
Suspended animation also seems to elongate lives: Animals that hibernate live longer, on average, than similar species that don’t hibernate. Of course, they don’t face many predators during their long winter sleeps, which helps. But biologists also suspect another reason: Hibernation slows down the shortening of telomeres, the caps on the ends of chromosomes that typically dwindle with age. Could it be that hibernation itself actually slows the aging process? That is a question for the future, and it speaks to the multitude of secrets in the seemingly simple act of curling up for a long winter’s rest. For his part, Andrews is optimistic: “I think we’ve just started to scratch the surface of how hibernation strategies can be applied to people.”