1. Cosmos 46 www.cosmosmagazine.com 7776 www.cosmosmagazine.com Cosmos 46
>>
getty/iSTOCK
Studying the physiology of hibernating bears offers insights that may
help treat people with such illnesses as diabetes and osteoporosis.
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.
O
N 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?

2. >>
78 www.cosmosmagazine.com Cosmos 46
>>
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.
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
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 brains.
Meanwhile, neonatologist
Marianne Thoresen at the University
of Bristol in England and anaesthetist
John Dingley at Swansea University’s
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 Michael’s 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 Riley’s brain reached 33.5°C. 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,”
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.”
“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.”olefrobert
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 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
olefrobert
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
wikimedia
Nerve cell
endings in
the brains
of ground
squirrels
change during
hibernation.
A technique
of cooling
the brain
is helping
newborns at
risk to avoid
permanent
brain damage.
istock

3. >>
Cosmos 46 www.cosmosmagazine.com 8180 www.cosmosmagazine.com Cosmos 46
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
Animals around the
world have evolved
ingenious ways to survive
environmental extremes,
reports Ola Jachtorowicz.
Common poorwill
Scientific name Phalaenoptilus nuttali
Location Western North America
Hibernates for up to 3 months
The only bird known to hibernate, the
poorwill doesn’t 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 Hölchoko or ‘the
sleeping one’.
American black bear
Scientific name Ursus americanus
Location North America
Hibernates for 5–8 months
Considered 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 slider
Scientific name Trachemys scripta
elegans
Location Southern U.S.
Brumates for 6–7 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 monte
Scientific name Dromiciops gliroides
Location South America
Hibernates for up to 4 months
A 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 30°C.
Black rockcod
Scientific name Notothenia coriiceps
Location Ocean around Antarctica
Hibernates for 6–8 months
In 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 isn’t due to water
temperature, but most likely to lack of light
during Antarctica’s long winter. It waits out
the darkness before resuming hunting prey.
Mountain pygmy possum
Scientific name Burramys parvus
Location Australia
Hibernates for 5–7 months
The critically endangered pygmy possum
burrows deep into snow and boulder crevices
in winter. Native to Australia’s alpine regions
and only 11cm long, it is the country’s only
hibernating marsupial.
>>
European hedgehog
Scientific name Erinaceus
europaeus
Location Western Europe
Hibernates for 5–7 months
These hedgehogs build nests in which
to hibernate when the temperature drops
below 16°C. While hibernating, they will still
bristle (erect their spines) when touched or
exposed to noise.
Northern bat
Scientific name Eptesicus nilssonii
Location Northern Europe to Japan
Hibernates for 4–8 months
Groups of two to four choose underground
spaces such as caves, mines, cellars
and bunkers. They can hibernate in
conditions below 0°C, which benefits them
energetically and enables them to hibernate
for up to eight months in a row.
Fat-tailed dwarf lemur
Scientific name Cheirogaleus medius
Location Madagascar
Aestivates for 6–8 months
This primate – the only tropical mammal
getty
wikimedia
wikimedia
getty
jillzamzow
wikimediawikimedia
wikimedia
getty
istoCk
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
brain activity.”
SETHDonahue

4. >>
82 www.cosmosmagazine.com Cosmos 46
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 – H2
S – induced a state
of reversible hibernation. H2
S 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 H2
S. 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.
H2
S 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
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 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
H2
S 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
Broadcasting Corporation.
“These are physiological feats
that humans could never survive.”
olefrobert