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Studying the physiology of hibernating bears offers insights
that may help treat people with such illnesses as diabetes and
As winter sets in, many animals effectively
shut down their bodies in order to survive.
Injured humans might benefit from similar
techniques, writes Zuberoa Marcos.
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
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
food is scarce and later return to an active state as if nothing
Its 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
Duluth in the U.S. Hibernators are so widespread in nature
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?
78 www.cosmosmagazine.com Cosmos 46
attack or a stroke, explains Ole Frbert, a cardiologist from
rebro University Hospital in Sweden. However, brown bears do not
suffer any of this.
How bears keep their arteries safe under these conditions is
what Frbert and his colleagues are investigating.
double its body weight by adding fat during summer and
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
Cosmos 46 www.cosmosmagazine.com 79
GROUND SQUIRRELS can teach us a lot about brain regeneration. In
2006, H. Craig Heller, a biologist at Stanford University in the
U.S., and his colleagues reported in The Journal of Neuroscience
that during hibernation, squirrel brains retract many of their
dendrites, the tendril-like nerve-cell endings that receive
information from other neurons. Yet each time the squirrels wake,
even for only a few hours, the dendrites regrow and even faster
than during embryonic development. Dendrite retraction also occurs
in humans as we age, so understanding how squirrels regenerate
their dendrites might help develop new therapies for damaged
Meanwhile, neonatologist Marianne Thoresen at the University of
Bristol in England and anaesthetist John Dingley at Swansea
School of Medicine in Wales have developed a pioneering
technique to save the lives of babies at risk of brain damage.
Riley Joyce was born in April 2010 at the Royal United Hospital,
Bath, without a pulse and not breathing, and with a 50% chance of
permanent brain injury. He was transferred to St Michaels Hospital,
Bristol, where Dingley used cooling and xenon gas to safeguard his
brain. Xenon is a very rare and chemically inert gas found in tiny
quantities in the air that we breathe, explains Thoresen. In lab
studies we have seen it doubles the protective effect of cooling on
the brain because it blocks a cell surface receptor whose
activation can lead to the death of nerve cells.
The scientists have spent more than 10 years developing the
technique, and Riley became the first in the world
upon whom it was tested. First, a cold cap slowly cooled his
head. Then a xenon breathing system, working in conjunction with a
mechanical lung ventilator, administered xenon into the lungs where
it is absorbed into the bloodstream, via which it reaches the
brain. The xenon was administered until Rileys brain reached 33.5C.
He was kept cool for 72 hours and then his brain was slowly
re-warmed. After seven days he was doing well and able to take milk
for the first time.
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, Frbert says. In his teams experiment, published online in
Clinical and Translational Science in January 2012, its not clear
how the animals keep their arteries flexible. Researchers hope to
find a molecule that could similarly affect humans blood
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.
Its not only the hibernators diet thats 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.
There is some kind of connection between hibernators and human
survivors, people who have cheated death after being submerged in
or buried in snow, without oxygen, for hours.O
Scientists from the Scandinavian Brown Bear Research Project
take blood and fat tissue samples from an anaesthetised hibernating
bear for analysis.
Breath samples are collected to characterise
brown bear metabolism.
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
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
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
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 animals body works changes when
it hibernates, however, and preparations start months in
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 bloodbrain
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
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
Consuming 0.20.3% 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
Nerve cell endings in the brains of ground squirrels change
A technique of cooling the brain is helping newborns at risk to
avoid permanent brain damage.
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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
HUMAN PARATHYROID hormone may not be as efficient as bears at
recycling minerals back into bones. Donahue and his team are
currently studying the hormones 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.
Donohues 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 -2.9C, 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,
As Andrews explains, these are physiological feats that
non-hibernating animals, including humans, could never survive. A
human will go hypothermic in [temperatures] around 32C. The
chemical reactions in our bodies just cant 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 37C for
Animals around the world have evolved ingenious ways to survive
environmental extremes, reports Ola Jachtorowicz.
COMMON POORWILLSCIENTIFIC NAME Phalaenoptilus nuttaliLOCATION
Western North AmericaHIBERNATES FOR up to 3 monthsThe only bird
known to hibernate, the poorwill doesnt build a nest but sits in
piles of rocks or clumps of grass, concealed by its camouflage
plumage. The Native American Hopi people called it Hlchoko or the
AMERICAN bLACK bEARSCIENTIFIC NAME Ursus americanusLOCATION
North AmericaHIBERNATES FOR 58 monthsConsidered highly efficient
hibernators or super-hibernators, black bears recycle their waste
into proteins, which become part of
their muscles. Females wake long enough to birth cubs and lick
them clean before resuming their slumber, while the cubs remain
awake, suckling their mother and waiting for spring.
RED-EARED SLIDERSCIENTIFIC NAME Trachemys scripta
elegansLOCATION Southern U.S. BRUMATES FOR 67 months Called sliders
for their ability to quickly evade predators by slipping off rocks
and logs and into the water, these turtles brumate (a reptilian
version of hibernation) through winter at the bottoms of ponds and
shallow lakes, occasionally rising for air.
MONITO DEL MONTESCIENTIFIC NAME Dromiciops gliroidesLOCATION
South AmericaHIBERNATES FOR up to 4 monthsA living fossil, the
monito del monte (little mountain monkey) is ancestral to
Australian marsupials. It spends its life in trees and bamboos of
Andean temperate rainforests, hibernating in well-hidden,
spherical, water-resistant nests lined with moss or grass.
known to aestivate, the heatwave equivalent of winter
hibernation holes up in tree trunks in groups of four to five.
Surviving on fat stored in its tail, the fat-tailed dwarf lemur
becomes dormant to combat drought, its body temperature varying
with the outside temperature reaching up to 30C.
bLACK ROCKCODSCIENTIFIC NAME Notothenia coriicepsLOCATION Ocean
around AntarcticaHIBERNATES FOR 68 monthsIn 2008, it became the
first fish identified to change its metabolic activity as part of
an annual cycle, becoming 20 times less active. Its dormancy
pattern isnt due to water temperature, but most likely to lack of
light during Antarcticas long winter. It waits out the darkness
before resuming hunting prey.
MOUNTAIN PYGMY POSSUMSCIENTIFIC NAME Burramys parvusLOCATION
AustraliaHIBERNATES FOR 57 monthsThe critically endangered pygmy
possum burrows deep into snow and boulder crevices in winter.
Native to Australias alpine regions and only 11cm long, it is the
countrys only hibernating marsupial.
EUROPEAN HEDGEHOGSCIENTIFIC NAME Erinaceus europaeus
LOCATION Western EuropeHIBERNATES FOR 57 months
These hedgehogs build nests in which to hibernate when the
temperature drops below 16C. While hibernating, they will still
bristle (erect their spines) when touched or exposed to noise.
NORTHERN bATSCIENTIFIC NAME Eptesicus nilssoniiLOCATION Northern
Europe to JapanHIBERNATES FOR 48 months Groups of two to four
choose underground spaces such as caves, mines, cellars and
bunkers. They can hibernate in conditions below 0C, which benefits
them energetically and enables them to hibernate for up to eight
months in a row.
FAT-TAILED DWARF LEMURSCIENTIFIC NAME Cheirogaleus
mediusLOCATION MadagascarAESTIvATES FOR 68 monthsThis primate the
only tropical mammal
Bears bodies continue to produce bone (shown here) during
hibernation. Instead of excreting minerals released from bones as
would normally happen during a period of non-activity, the bears
bodies instead re-absorb them into the kidneys with the help of two
chemical compounds. Research into this process could lead to
breakthroughs in the treatment of osteoporosis in humans.
Scientists in Pittsburgh revived
dogs after three hours of clinical
death no heartbeat, no breathing and no
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1220 hours, then goes into hibernation again without any tissue
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 mices core body
temperature and makes animals enter hibernation.
Five-prime AMP is part of a cellular process called oxidative
phosphorylation, which is the bodys power-generating apparatus.
Cells need oxygen to make adenosine triphosphate, or ATP, the
primary fuel of life. As the organisms 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
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 22C. 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 10C.
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 teams 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 20C 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
H2S seems to slow, or even stop, oxidative phosphorylation, the
process by which cells produce energy. Roths 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 Roths
team focusses on slowing the metabolic rate and the temperature
comes down as a by-product, Kochaneks 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
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 10C.
Most of the time people with severe trauma and blood loss dont
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
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
Some bears can double their body weight during summer in
preparation for winter hibernation.
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.
just 15 minutes this way, adds Tisherman. A heartlung 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
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.
Zuberoa Marcos is a barcelona-based science writer and
scientific director of a weekly tV magazine at the Spanish
These are physiological feats that humans could never