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2014-05-07 13:32:07
Frank Swain
The extreme survival tricks of hibernating animals and the occasional human
could help us overcome life-threatening injuries, as Frank Swain discovers.
Imagine it: you have been rushed into the emergency room and you are dying.
Your injuries are too severe for the surgeons to repair in time. Your blood
haemorrhages unseen from ruptured vessels. The loss of blood is starving your
organs of vital nutrients and oxygen. You are entering cardiac arrest.
But this is not the end. A decision is made: tubes are connected, machines whir
into life, pumps shuffle back and forth. Ice-cold fluid flows through your
veins, chilling them. Eventually, your heart stops beating, your lungs no
longer draw breath. Your frigid body remains there, balanced on the knife-edge
of life and death, neither fully one nor the other, as if frozen in time.
The surgeons continue their work, clamping, suturing, repairing. Then the pumps
stir into life, coursing warm blood back into your body. You will be
resuscitated. And, if all goes well, you will live.
Suspended animation, the ability to set a person s biological processes on
hold, has long been a staple of science fiction. Interest in the field
blossomed in the 1950s as a direct consequence of the space race. Nasa poured
money into biological research to see if humans might be placed in a state of
artificial preservation. In this state, it was hoped, astronauts could be
protected from the dangerous cosmic rays zapping through space. Sleeping your
way to the stars also meant carrying far less food, water and oxygen, making
the ultimate long-haul flight more practical.
There has long been interest in whether suspended animation could allow
astronauts to survive missions to Mars and beyond (Science Photo Library).
One recipient of that funding was a young James Lovelock. The scientist would
dunk hamsters into ice baths until their bodies froze. Once he could no longer
detect a heartbeat, he would reanimate them by placing a hot teaspoon against
their chest (in later experiments, Lovelock warmed to the space-age theme by
building a microwave gun out of spare radio parts to more gently revive his
test subjects). These experiments on the flexibility of life would set him on
the path to his most famous work, the Gaia hypothesis of the world as a
living super-organism.
Adventurous as they were, these early experiments did not progress beyond the
animal stage, and astronauts were never frozen and revived with hot spoons. The
idea of transforming people into inanimate bars of flesh for long-distance
space travel remained in the realm of science fiction. Nasa s interest tailed
off with the end of the space race, but the seeds planted by Lovelock and his
colleagues continued to grow.
Cold storage
In 1900, the British Medical Journal published an account of Russian peasants
who, the author claimed, were able to hibernate. Existing in a state
approaching chronic famine , residents of the north-eastern Pskov region would
retreat indoors at the first sign of snow, and there gather around the stove
and fall into a deep slumber they called lotska . Waking once a day to wash
some hard bread down with water, the family took it in turns to watch the fire,
only rousing themselves fully once spring had broken. No trace of the sleepy
peasants of Pskov has ever emerged since, but the fantasy of human hibernation
persists, and very occasionally, something that looks very similar to it
crosses into reality.
A century later, Anna Bagenholm was on a skiing holiday in Norway when she
crashed head first into a frozen stream and became trapped under the ice. When
rescuers finally arrived, the Swedish radiologist had been submerged for 80
minutes, and her heart and breathing had stopped. Doctors at Tromso University
Hospital recorded a body temperature of 13.7C, the lowest ever observed in a
victim of accidental hypothermia. By all accounts she appeared to have drowned.
And yet, after careful rewarming and ten days spent in intensive care,
Bagenholm woke up. She went on to recover almost fully from her cold brush with
death. Under normal circumstances, even a few minutes trapped underwater would
be enough to drown a person, and yet Bagenholm had survived for over an hour.
Somehow the cold had preserved her.
It s not the first time the benefits of cold for traumatic injury have been
made apparent. As far back as the Napoleonic era, medics noted that wounded
infantrymen left out in the cold had better survival rates than the wounded
officers kept close to the fire in warmed tents. Therapeutic hypothermia is now
commonly used in hospitals to reduce injury in a wide variety of situations,
from surgery to helping infants recuperate following difficult births.
Lowering your body temperature slows your metabolic activity, about 5 7% for
every degree dropped. This in turn reduces the rate at which you consume
essential nutrients such as oxygen. Tissues that might become starved of oxygen
due to blood loss or cardiac arrest are thus protected. In theory, if we were
to keep reducing your temperature, eventually your biological processes would
come to a standstill. You would exist in a state of suspended animation. Like a
stopped clock, there d be nothing physically wrong with you all the
components inside would still be intact, simply stationary. All it would take
would be a little heat to set you in motion again.
Of course, it s not that simple. Hypothermia is dangerous. Your body wants to
be warm and will fight to remain that way. Throughout your life, it will
maintain a fairly constant temperature of around 37C. This requires great
effort. Your body must perform countless constant adjustments to balance heat
production with heat lost to the environment, working to keep your temperature
within a narrow band. If it drops too low, your blood is shunted away from the
exposed skin and gathers in your central torso while you shiver and huddle
under blankets. The effects of more severe cold are disastrous. At a body
temperature of around 33C just four degrees below normal your heartbeat
begins to flutter. At 25C, there s a risk it will stop altogether. And even if
you survive hypothermia, warming you up again can cause extensive kidney
damage.
Arctic ground squirrels make sure their bodily fluids don t freeze solid during
hibernation (Science Photo Library)
There are, however, certain species of animal that can endure far greater
spells of cold. The Arctic ground squirrel normally maintains a body
temperature similar to our own. But during hibernation, it can survive a core
temperature as low as 3C, carefully managing its super-cooled bodily fluids so
that it won t freeze solid. And Lovelock s hamsters could survive hypothermic
depths that would kill us. How animals survive these states is of great
interest to anyone hoping to unlock the secrets of suspended animation for
humans.
Staying alive
When is your comrade dead? asks Professor Rob Henning with a grin, quoting an
Army handbook he received as one of the Netherlands last draft of conscripts.
One: Is he rotting? Two: Is his head more than twenty centimetres from his
body? Like Lovelock, Henning has conducted experiments with hibernators that
have given him a flexible view of what constitutes being alive.
From the top floor of the Department of Clinical Pharmacy and Pharmacology at
the University Medical Centre Groningen (UMCG), a large window looks down on
the medieval city spread over a pancake-flat landscape. Below is a bustling
hospital, the region s hub for transplant surgery. It s also where Henning and
his team are uncovering the secrets of hibernation.
What we re doing here is biomimicry, says Henning, using these great
adaptations in nature to hijack them for the benefit of medicine.
Many animals can slow their metabolism to enter low-energy states: insects,
amphibians, mammals, birds and fish. In short periods, this condition
characterised by reduced body temperature and inactivity is known as torpor.
By stringing together many of these short sessions of torpor, animals can enter
the long-term dormancy we call hibernation. With this technique, small animals
such as mice, hamsters and bats can last out the cold famines of winter huddled
away, conserving energy.
Trained as an anaesthetist, Henning started hobbying in hibernation in the
1990s, but things took off in earnest when his research group was formed around
six years ago. If you think about hibernators, you have a lot of applications.
The most obvious ones are any type of major surgery, he explains. Blood loss
is the major cause of death during surgery, but in their hypothermic state,
hibernators can survive far worse injuries than they can at normal body
temperatures. This is partly because tissues are protected at low metabolic
rates, and partly because the heart is pumping blood at a fraction of the rate
it usually does.
A dormouse in torpor. It will spend up to three quarters of its life asleep,
hibernating (Science Photo Library)
But a resistance to cold and blood loss isn t the total sum of hibernators
incredible endurance. Although it resembles a very long lie-in, hibernating is
not a simple matter of sleeping through the cold. It s a gruelling marathon of
hypothermia, starvation and disease susceptibility. To endure these sufferings,
the animals that practice it have developed a suite of adaptations to protect
mind and body.
Before a long hibernation, animals eat their way into obesity, essentially
becoming type 2 diabetic. Unlike in humans, this does not result in the
thickening of artery walls that leads to heart disease. Some species will stop
eating two or three weeks before hibernation, suddenly resistant to the pangs
of hunger even while maintaining their regular level of activity.
While a human can lie in bed for a week before muscles begin to atrophy and
blood clots form, hibernators will endure months without moving. During
hibernation, the microbiome the community of bacteria living in an animal s
digestive tract is battered by cold and the sudden lack of food. Hibernators
lungs become covered with a thick deposit of mucus and collagen like those seen
in people with asthma, and their brains show changes that resemble those of
early-stage Alzheimer s. Some species lose memory during hibernation. Most
surprising of all, some show symptoms of sleep deprivation when they finally
wake. And yet, hibernators are able to counter all of these issues to bounce
back in spring, often without any long-term ill effects.
Thicker than water
UMCG is a half-kilometre complex of buildings so tightly huddled together that
it s possible to walk from the grand foyer at one end to the bicycle racks at
the other without stepping outside. One of these buildings is the animal
laboratory.
In a tiny room set away from the main corridor, Henning s doctoral student
Edwin de Vrij and his colleague are tending to a rat laid prone on a bed of
ice. A tangle of fine tubes and wires surrounds the animal, delivering
life-preserving fluids and carrying away precious data. A spool of paper
inching from one machine shows that from a frenetic 300 beats per minute, the
rat s heart rate has slowed to just 60. The red numbers glowing on another show
that the rat s internal temperature has dropped more than 20 degrees to 15C.
Clicking like a metronome, a ventilator delivers steady breaths to the
anaesthetised rodent. As a non-hibernator like us, the rat cannot survive deep
hypothermia without medical assistance. If you cool them down, nerve impulses
will be slower, and muscles have a harder time in the cold, so it s quite
physiological that they have a harder time breathing, explains de Vrij. This
isn t the case for true hibernators or some other non-hibernating mammals,
for that matter. Somehow hamsters can maintain adequate breathing, he says.
We don t have to ventilate them.
As well as inducing hibernation in hamsters (a process that takes weeks of
gradual adjustment in climate-controlled rooms to mimic the onset of winter),
the UMCG team also induce forced hypothermia states like that of our rat,
chilling the animals rapidly until they fall into a state of metabolic
suspension.
Today, de Vrij is searching for platelets, which are essential for blood
clotting to prevent bleeding. Hibernating animals avoid getting blood clots
despite their lack of activity, an ability that comes down partly to a curious
change in the hypothermic body: as they cool, platelets disappear from the
blood. Nobody yet knows where they go, but their prompt reappearance on
rewarming has de Vrij convinced that they are preserved somewhere in the body,
rather than being absorbed and later resynthesised. Surprisingly, this change
also happens even in non-hibernators, including rats and occasionally human
victims of hypothermia.
Platetets (pink) are vital for blood clotting, and could play a key role in
helping animals survive during hibernation (Science Photo Library)
The shared characteristics of different hibernators mean it s likely that these
species have inherited fragments of protective mechanisms against cold,
inactivity, starvation and asphyxiation from common ancestors and developed
these into a comprehensive low-metabolic syndrome. There are even hints that we
humans might, to some extent, retain some of these abilities. For a long time,
there was no evidence that primates could hibernate. But in 2004, a species of
Madagascan lemur was shown to practice regular bouts of torpor. If you look at
the lemur and look at us, we share about 98% of our genes, says Henning. It
would be very strange if the tools of hibernation were all packed into that 2%
difference.
As their body temperature drops, hibernators also remove the lymphocytes (white
blood cells) from their blood and store them in the lymph nodes. And within 90
minutes of awakening, these reappear. This damping down of the immune system
prevents a general inflammation in the body during rewarming the very thing
that would cause humans and other non-hibernators to suffer kidney damage.
However, it s a risky strategy, leaving animals unable to mount an immune
defence while hibernating. The fungus responsible for white-nose syndrome,
currently wiping out bat colonies in the USA, takes advantage of this
vulnerability, infecting the bats while they are dormant. In response, the bats
frequently exit hibernation and rewarm to fight off the pathogen the
high-energy cost of these interruptions ultimately killing them.
Funny smell
Knowing how hibernators control these changes in their blood could have
immediate and far-reaching benefits for us. As well as improving our ability to
survive hypothermia and cold suspended-animation states, stripping the blood of
white blood cells could prevent the aseptic sepsis caused by heart lung
machines, in which activation of blood cells as they pass through the
life-support equipment triggers a body-wide immunological reaction. Transplant
organs, often chilled for transport, would also benefit from better
cryoprotection. And we could increase the shelf-life of our blood stocks we
still haven t figured out how to store donated blood platelets at low
temperatures, so blood donations can only be kept a week before they must be
used or thrown away due to the risk of bacterial infection.
The UMCG team took a giant leap towards achieving these goals quite by accident
after a student left a culture of hamster cells in a fridge at 5C. After a week
the hamster cells were still alive, and smelling of rotten eggs. The student
poured the medium surrounding the cells over a separate batch of cells from a
rat, suspecting the smelly cells might have secreted some kind of protective
agent. She placed them in the same fridge and waited. Normally, refrigerating
rat cells would quickly kill them, but after two days they were still alive.
The team is investigating several compounds that might be responsible for this
cryopreservation. One is an enzyme known as cystathionine beta synthase (CBS),
which stimulates the production of hydrogen sulphide, the molecule that gives
rotten eggs their characteristic whiff. If hamsters are injected with a
chemical to inhibit CBS, they can no longer enter torpor, and those that were
forced into hypothermic states suffered the kind of kidney damage one would
expect in non-hibernators like us.
Of over a hundred compounds Henning s team has investigated, many had no
effect, but a few did, conferring long-term cold protection to cell samples.
The team has already patented one of these compounds, Rokepie, as an additive.
This would allow cells that normally need to be kept at 37C, such as those from
humans or mice, to be stored in the refrigerator, either for transport or so
experiments can be put on hold during weekends and busy periods.
The leading cryopreservation molecules extracted from hibernators are
incredibly potent, and it seems they work by eliciting changes in the cells
themselves whether these are from hibernators or not. If so, this offers
further evidence that we still possess some tools that could help endure
hypothermia and low metabolic states.
For now, applying the lessons they ve learned from hibernators wholesale onto
humans is not within the remit of Henning s group. The space race is long over,
and Nasa is not awarding major grants to develop suspended animation. However,
the US Army is.
Golden hour
If you look anywhere near a trauma bay, things are pretty chaotic, says
Professor Sam Tisherman. It s controlled chaos, but the chaos mainly comes
from the fact you never know what s going on with the patient.
In frenetic hospital emergency wards, it s often not possible for doctors to
identify the problem, fix it and keep the patient alive all at the same time.
Patients suffering uncontrolled blood loss, for example, may go into cardiac
arrest. When this happens, surgeons must fight the clock to stop the bleeding
before they can start resuscitation efforts. Somebody rolls in and they re
basically dying, says Tisherman. We re quickly trying to resuscitate them,
and figure out what s wrong with them, and repair injuries all at the same
time. This is the fundamental underpinning of trauma medicine: you are always
against the clock.
Tisherman wants to buy doctors a little more time. He believes that by inducing
hypothermia we can extend the golden hour in which surgeons battle to save
the lives of critically injured patients. To do this, he s pushing human
endurance of hypothermia far beyond its normal limits.
After graduating from MIT in 1981, Tisherman built a career in critical care
medicine. He won a Lifetime Achievement Award in Trauma Resuscitation Science
from the American Heart Association in 2009, and is now an Associate Director
of the Safar Center for Resuscitation Research in Pittsburgh. It was founded by
Peter Safar, the Austrian physician who popularised the kiss of life , CPR,
and drove the creation of the Resusci Anne doll used in teaching it. At
Pittsburgh, Safar created the world s first intensive care training programme.
His lifelong aim was to save the hearts and brains of those too young to die.
The procedure that Tisherman is pioneering is called emergency preservation and
resuscitation. His work is supported through the US Army s Telemedicine and
Advanced Technology Research Center, which funds research on topics as niche as
advanced prosthetics and robots to carry wounded soldiers out of the
battlefield.
Some of his surgeons will already be familiar with hypothermic techniques,
having routinely chilled patients to the low 30s or high 20s. For procedures
that require zero blood flow, cardiac surgeons will even cool patients to
around 15C, the point at which their heart stops.
Surgeons performing a cardiac operation using hypothermic protection of the
patient in Russia in 1979 (Science Photo Library)
Tisherman is planning to cool patients to this point, and perhaps even further,
chilling them to such a degree that the entire body enters a kind of suspended
animation. During this time, they will have no heartbeat, no breathing and no
discernible brain activity. In fact, they ll have no blood, either it will be
drained and replaced with ice-cold saline, the only way to cool a human fast
enough to avoid tissues becoming damaged as they struggle to remain
functioning. Tisherman calls this state hypothermic preservation .
The procedure has already been demonstrated successfully in the lab, reviving
dogs that had lain suspended in cold states for up to three hours. Trials are
now moving to a clinical setting. Surgeons, anaesthetists and perfusionists at
Massachusetts General Hospital have even undergone training for the pioneering
surgery. But no one knows when a suitable patient will arrive through the
doors. That is in fact one of the issues they face: by the nature of trauma,
patients won t be able to give informed consent for the procedure. Because of
this, Tisherman s group has engaged in a wide community consultation to let
citizens in the area know the programme was going on. The study had to be
signed off personally by the Secretary of the Army, the highest-ranking
civilian official in the organisation.
Beyond that lie further obstacles. Amid the frantic activity of the emergency
room, Tisherman must make sure that a team of trauma surgeons can work in
concert with cardiac surgeons and perfusionists armed with pumps and bags of
chilled saline, an additional layer of complexity in an already chaotic
environment. And although cooling affects all tissues equally, it is not
without secondary effects. The blood factors responsible for clotting are also
inhibited by the cold. This creates problems controlling bleeding during the
rewarming phase. The surgeons, too, will suffer from the cold, as both the
patient and the room itself will be chilled during the procedure. Yet the cold
is only a tool; the end goal is metabolic suspension.
In the future, emergency preservation and resuscitation could be extended to
those suffering heart attacks or exposure to poisons, or any critical care
situation where time is a factor. Cooling is the most powerful way of
suppressing metabolism we have, says Tisherman, If we can either decrease the
needs of the tissues or improve oxygen delivery to the tissues then everything
will be okay.
Although animals in the laboratory were able to recover from three hours in
this suspended state, the first human patients to experience it will only be
put under for a third of that. An hour should be enough to repair the
bleeding, Tisherman says. The cooling period doesn t necessarily have to
cover the entire surgery. For those wanting to travel to distant stars, going
beyond that hour is, sadly, out of the question for now. We re not trying to
freeze the dead, Tisherman chuckles, just buy enough time to save the living.