Total shutdown: hibernation for humans

On long, dark and cold winter days, you probably like to go to bed early and find it hard to get up in the morning. Humans survive the winter by rugging up well, switching on the reverse-cycle air-conditioning, and moving from heated cars to heated offices.

Animals survive the winter by migrating to where the weather is milder, by remaining active but thickening their ‘coat’ or by changing their diet. But the most extreme method is to completely shut themselves down.

For five to seven-and-a-half months of the year, black and brown bears turn themselves off. They do not eat, drink, urinate, defecate or exercise. They reduce their metabolism by 50 to 75% of normal rates. They breathe once every 15 to 60 seconds and their heart rate drops from around 50 to about 10 beats per minute.

Hibernation is a strategy to combat extreme environmental conditions. By setting the body metabolism to a kind of slow motion, some animals reduce their energy costs by more than half when food is scarce and later return to an active state as if nothing happened.

It’s a strategy also used by squirrels, marmots, hedgehogs, bats and even the fat-tailed dwarf lemur of Madagascar. “All land-dwelling mammals except ungulates [mostly hoofed mammals] and lagomorpha [hares and rabbits] have at least one hibernating species,” says molecular biologist Matthew Andrews, who has studied hibernation for the past 12 years at the University of Minnesota Duluth in the U.S. Hibernators are so widespread in nature that scientists think that the genetic hardware required to go into hibernation is common among all mammals. So why is it that some species hibernate and some do not?

There is an evolutionary explanation for this, says Andrews. “Humans are largely a tropical species. We evolved in the tropics where food is generally available. We have very thin skin because we had little need to protect ourselves from the cold. If we had evolved in Siberia or Northern Canada we might have [developed] an ability to hibernate because we would be subjected to a limited growing season.”

Since the late 1800s, scientists have tried unsuccessfully to unlock the inner workings of hibernation. Yet molecular biology is slowly unravelling the mysteries of this phenomenon. The spin-off is a deeper understanding of controversial medical technologies that can slow patients’ respiration to almost zero – and bring them back from near death.

Every animal on Earth burns fuel to get the energy to walk, breathe, sleep and keep their bodies at optimal temperatures. Nearly everything about the way an animal’s body works changes when it hibernates, however, and preparations start months in advance.

When there is no fruit on the trees and no prey to catch and eat, “hibernators take their own fat and break it up to produce ketone bodies, four-carbon molecules that cross the blood–brain barrier and fuel the brain and the rest of the organs,” Andrews says. “The switch-over of metabolism to use fat instead of carbohydrates as primary fuel for the body is the main task of hibernators.”

As with most biological processes, hibernation is directed by the products of genes, specifically enzymes. Two enzymes, PDK4 and PTL, are partially responsible for the fuel switch that is seen in hibernating animals, as first described by Andrews and his colleagues in a 1998 research article published in the Proceedings of the National Academy of Sciences. PDK4 stops carbohydrate metabolism in order to preserve the glucose that animals have stored from their last meal. PTL is responsible for starting up the mechanism to convert fat into usable energy at low body temperatures.

Consuming 0.2–0.3% of their body mass per day, hibernators can survive until spring. And the bigger their fat stores, the greater their chances of getting through the winter – for example, a bear is able to double its body weight by adding fat during summer and autumn.

“The cholesterol levels in their blood are double that of humans and their heart beats very, very slowly which is also a risk factor for blood clotting. These conditions [would] put a person on the verge of a heart attack or a stroke,” explains Ole Fröbert, a cardiologist from Örebro University Hospital in Sweden. “However, brown bears do not suffer any of this.”

How bears keep their arteries safe under these conditions is what Fröbert and his colleagues are investigating.

Finding the answer is risky. Bears are dangerous animals. Even when hibernating, they can wake suddenly and attack unwanted visitors. So scientists use radio transmitters or GPS devices to locate previously tagged bears in the wilds of Sweden, and tranquilise the animals with darts before approaching. Then, they take blood samples and fat tissue biopsies. Artery samples are collected from bears killed during the legal hunting season.

“We have found that the levels of ‘good’ and ‘bad’ cholesterol are both increased in bears’ blood. This may have some protective effect,” Fröbert says. In his team’s experiment, published online in Clinical and Translational Science in January 2012, it’s not clear how the animals keep their arteries flexible. Researchers hope to find a molecule that could similarly affect humans’ blood vessels.

The secret may be in the animals’ diet. “The fat that hibernators use is very different from the fat humans consume – we often eat saturated fats,” says Andrews. “These animals eat seeds, ‘good’ fats, unsaturated vegetable fats and they also do a good job of producing omega-3 and omega-6 fats, which have beneficial effects on cardiovascular systems.”

It’s not only the hibernators’ diet that’s desaturated. They are also pretty good at desaturating the fats in their bodies.
“If fats are saturated they will solidify, turn into butter at low body temperatures” so the animals could not use them, says Andrews. “But being unsaturated they stay liquid even in a very cold environment.” How they do it is what he and other researchers want to understand. “Hibernators selectively use fat all winter long and, despite the extra pounds, they stay healthy. This could help us combat obesity and diabetes in humans.”

Cholesterol-defying arteries are not the only evolutionary trick scientists are trying to understand. Colorado State University biomedical engineer Seth Donahue studies how hibernators preserve muscle tone and bone strength despite several months of inactivity each year.

People normally lose bone as they age. Studies have shown that after menopause, women lose 1 to 2% of their bone mineral density per year. Bedridden patients may lose 3 to 4% of their skeletal mass each month. Hibernators, on the other hand, wake up from their long-term dormancy with their skeletons and muscles unaffected. In the case of the squirrels, they have no option if they want to avoid being eaten by foxes and panthers – they have to stay strong and mobile and have developed the genetic ability to do this.

Monitoring bone metabolism markers in the blood of five bears, Donahue found that “during hibernation, bone loss and bone breakdown do happen but bears have developed the biological mechanism to [keep] bone production constant”. In a 2008 review published in the American Journal of Physiology, he and his colleagues found this is due to the high levels of two chemical compounds, osteocalcin and parathyroid hormone, or PTH.

“Just as in humans, bear bones release minerals during periods of inactivity. But instead of excreting calcium, PTH induces its re-absorption by the kidneys and puts it back in bears’ skeletons,” Donahue says. “Osteocalcin is a protein normally excreted in the urine. Since bears do not urinate during hibernation, osteocalcin levels increase and contribute to bone mineralisation and building.”

Human Parathyroid hormone may not be as efficient as bears’ at recycling minerals back into bones. Donahue and his team are currently studying the hormone’s bone-sparing power. “We have sequenced the gene for bear PTH, and used it to produce a synthetic form of bear PTH and reverse bone loss in rodent models of osteoporosis,” says Donahue.

Donohue’s team used rats with surgically removed ovaries, which simulates menopause, making their bones develop osteoporosis and become spongy. Next, they were injected with either human or bear PTH and had their bone density measured and compared over several weeks. Bones became stronger in the rats that had received the bear PTH. These results might lead to more effective treatments for osteoporosis in post-menopausal women, who are susceptible to bone loss.

Another hibernating animal that has caught scientists’ attention is the arctic ground squirrel, Spermophilus parryii. From early September to late April this small, orange and white squirrel cools its body to a core temperature of -2.9ºC, which is the lowest known naturally occurring temperature in mammals. At the same time, however, it keeps its brain, and other parts of the body involved in regulating and maintaining energy metabolism, above zero.

As Andrews explains, these are physiological feats that non-hibernating animals, including humans, could never survive. “A human will go hypothermic in [temperatures] around 32ºC. The chemical reactions in our bodies just can’t take place,” he says. Yet the cunning arctic ground squirrel is not only able to cool and heat up its body each year – during hibernation, every week or so, the squirrel stirs, shivers without waking, re-warms to 37ºC for about 12–20 hours, then goes into hibernation again without any tissue damage.

Scientists have identified several compounds that may explain how this is possible. Andrews has found that PDK4 and PTL, the same enzymes that switch over metabolism, help cardiac physiology to work at low temperatures. “PTL is a protein produced in the human pancreas but we have found it in the squirrels’ heart. The reason is that it works very well in the cold. It can burn fat in the cold and allow the heart to continue beating.”

In 2007, Tom Scanlan, a biologist now at Oregon Health and Science University in Portland, Oregon, published research in Stroke describing how a derivative of thyroxine, a thyroid hormone, rapidly lowers body temperature and slows heart rate when injected into rodents. Six to eight hours after injection, they resumed normal core body temperature and behaviour. The team has produced several similar synthetic substances that show the same or even more potent induction of hypothermia. Meanwhile, in 2006 in Nature, Cheng Chi Lee, a molecular biologist at the University of Texas in Houston, with his colleagues showed that the 5’-AMP (five-prime adenosine monophosphate) molecule also lowers mice’s core body temperature and makes animals enter hibernation.

Five-prime AMP is part of a cellular process called oxidative phosphorylation, which is the body’s power-generating apparatus. Cells need oxygen to make adenosine triphosphate, or ATP, the primary fuel of life. As the organism’s body cools, it needs less oxygen, oxidative phosphorylation slows down or stops, and the animal simply rests. This process happens not only in mice, but also in squirrels and other hibernating mammals. Perhaps even in humans.

In October 2006, the first known case of a human going into ‘hibernation’ was described. After slipping and breaking his pelvis, a 35-year-old hiker survived 24 days in a mountain forest without food or water. Mitsutaka Uchikoshi was found unconscious on Rokko Mountain in Japan, with a body temperature close to 22ºC. He had a weak pulse and was suffering blood loss. After referral to a hospital, he made a full recovery. His physicians believed his survival was a result of a cold-induced state similar to hibernation, as the mountain temperature dropped as low as 10ºC.

“I am convinced there is some kind of connection between hibernators and human survivors, people who have cheated death after being submerged in icy water, or buried in snow, without oxygen, for hours,” says Andrews.

A lack of oxygen often kills people who have had a cardiac arrest or a stroke. About five years ago, doctors began to experiment with therapies to cool down, even temporarily, such patients’ bodies and reduce their need for oxygen. The results have been nothing short of extraordinary.

In 2005, biochemist Mark Roth made headline news worldwide when Science published his team’s results showing that exposing mice to tiny doses of hydrogen sulphide – H2S – induced a state of reversible hibernation. H2S is a foul-smelling, corrosive, flammable and deadly gas, produced naturally in tiny amounts in the bodies of humans and other animals. In humans, it enables core temperature to stay uniform regardless of whether we are in the Arctic or the Caribbean.

At his lab at the Fred Hutchinson Cancer Research Centre in Seattle, Washington, Roth placed mice inside tanks from which nearly all of the oxygen had been removed and made them breathe 80 parts per million of H2S. Their core body temperature plunged 20°C within minutes, their heart rate declined more than 50% and their metabolic rate tumbled. The animals stayed in suspended animation for up to six hours before the oxygen supply was turned back on. Surprisingly, they woke up with no brain damage.

H2S seems to slow, or even stop, oxidative phosphorylation, the process by which cells produce energy. Roth’s experiment showed that mice can survive when exposed to low oxygen concentrations that would otherwise be lethal to them. He is also one of a number of researchers who are investigating the use of suspended animation in radical medical therapies.

In February 2008, anaesthetist Patrick Kochanek of the Safar Centre for Resuscitation Research at the University of Pittsburgh at Titusville, Pennsylvania, and his colleagues published a paper in the Journal of Cerebral Blood Flow and Metabolism describing how he had revived dogs after three hours of clinical death – no heartbeat, no breathing and no brain activity. While Roth’s team focusses on slowing the metabolic rate and the temperature comes down as a by-product, Kochanek’s team cooled the body in order to slow down the metabolic rate. They drained the dogs’ blood and replaced it with a solution of low-temperature glucose, dissolved oxygen and saline. The dogs came back to life after a blood transfusion and an electric shock to the heart, though a few suffered minor brain damage. Using a similar approach, a group of trauma surgeons at Massachusetts General Hospital in Boston reported successful results in several experiments with Yorkshire pigs.

The next step is to test suspended animation in humans. When a person has severe trauma and massive blood loss, oxygen supply also falls. When deprived of oxygen, an average person suffers brain damage within five minutes and dies 15 minutes later. But restoring blood flow is dangerous too. The influx of oxygen-rich blood produces so-called reactive oxygen molecules that can damage proteins and DNA and lead to cell death, contributing to tissue damage or organ failure.

Later in 2012, surgeon Samuel Tisherman and his team, also at Safar Centre in Pittsburgh, will start a clinical trial to see if they can rescue patients who have suffered cardiac arrest due to massive bleeding, by chilling them to nearly 10°C.

“Most of the time people with severe trauma and blood loss don’t survive,” says Tisherman. “Rapid cooling might be able to sustain the patient, particularly the brain, long enough to buy time for surgeons to find the source of blood loss, repair the wound and restore heartbeat.”

In the trial, body temperature will be lowered by administering up to 20 litres of cold fluid through a large tube placed into the aorta, the largest artery in the body. “In the preclinical studies we have done in animals, we have cooled down the body in just 15 minutes this way,” adds Tisherman. A heart–lung bypass machine will be used to restore blood circulation and oxygenation as part of the resuscitation process.

Extreme cooling therapy – expanding across hospitals even before scientists and doctors completely understand how it works – could also help treat some type of poisonings, for which blood circulation must be stopped. The power of H2S to induce hypothermia is also being tested in patients with acute lung injury, multiple organ failure and some inflammatory diseases. However, failure to reproduce the effects seen in mice in larger animals (such as sheep), as well as safety concerns, mean further research is needed.

Andrews remains optimistic. “In the future maybe we will have the ability to create transgenic hibernators, as we now create transgenic mice, to better understand how hibernation works.”