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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
getty/iSTOCK




                                                                                                                                                          scientists think that the genetic hardware
                                                                                                                                                        required to go into hibernation is common
                                                                                Studying the physiology of hibernating bears offers insights that may   among all mammals. So why is it that some
                                                                                  help treat people with such illnesses as diabetes and osteoporosis.   species hibernate and some do not?               >>



               76	   www.cosmosmagazine.com 	   Cosmos 46   Cosmos 46	                                                                                                   www.cosmosmagazine.com	   77
A technique
                                                                                                                                                                                                                                    of cooling
                                                                                                                                                                                                                                    the brain
        There is an evolutionary explanation for
>>
                                                                                                                                                                                                                                    is helping
     this, says Andrews. “Humans are largely a                                                                                                                                                                                      newborns at




                                                                                                                                                                                                                                                    istock
     tropical species. We evolved in the tropics                                                                                                                                                                                    risk to avoid
                                                                                                                                                                                                                                    permanent
     where food is generally available. We have                                                                                                                                                                                     brain damage.
     very thin skin because we had little need
     to protect ourselves from the cold. If we                                                                                                                                     GROUND SQUIRRELS can teach us            School of Medicine in Wales have          Nerve cell
     had evolved in Siberia or Northern Canada                                                                                                                                     a lot about brain regeneration. In       developed a pioneering technique          endings in
                                                                                                                                                                                                                                                                      the brains
     we might have [developed] an ability to                                                                                                                                       2006, H. Craig Heller, a biologist       to save the lives of babies at risk of    of ground
     hibernate because we would be subjected to                                                                                                                                    at Stanford University in the U.S.,      brain damage. Riley Joyce was born        squirrels
     a limited growing season.”                                                                                                                                                    and his colleagues reported in The       in April 2010 at the Royal United         change during




                                                                                                                                                                                                                                                                                      wikimedia
        Since the late 1800s, scientists have                                                                                                                                      Journal of Neuroscience that during      Hospital, Bath, without a pulse and       hibernation.
     tried unsuccessfully to unlock the inner                                                                                                                                      hibernation, squirrel brains retract     not breathing, and with a 50% chance
     workings of hibernation. Yet molecular                                                                                                                                        many of their dendrites, the tendril-    of permanent brain injury. He was
     biology is slowly unravelling the mysteries                                                                                                                                   like nerve-cell endings that receive     transferred to St Michael’s Hospital,
     of this phenomenon. The spin-off is a                                                                                                                                         information from other neurons. Yet      Bristol, where Dingley used cooling
     deeper understanding of controversial                                                                                                                                         each time the squirrels wake, even       and xenon gas to safeguard his brain.     upon whom it was tested. First, a cold
     medical technologies that can slow patients’                                                                                                                                  for only a few hours, the dendrites      “Xenon is a very rare and chemically      cap slowly cooled his head. Then a
     respiration to almost zero – and bring them                                                                                                                                   regrow… and even faster than during      inert gas found in tiny quantities in     xenon breathing system, working in
     back from near death.                                                                                                                                                         embryonic development. Dendrite          the air that we breathe,” explains        conjunction with a mechanical lung
                                                                                                                                                                                   retraction also occurs in humans         Thoresen. “In lab studies we have         ventilator, administered xenon into
     EVERY ANIMAL ON EARTH burns                                                                                                                                                   as we age, so understanding how          seen it doubles the protective effect     the lungs where it is absorbed into the
     fuel to get the energy to walk, breathe,                                                                                                                                      squirrels regenerate their dendrites     of cooling on the brain because it        bloodstream, via which it reaches the
     sleep and keep their bodies at optimal                                                                                                                                        might help develop new therapies for     blocks a cell surface receptor whose      brain. The xenon was administered
     temperatures. Nearly everything about the            Scientists from the Scandinavian Brown
                                                                                                                                                                                   damaged brains.                          activation can lead to the death of       until Riley’s brain reached 33.5°C. He
     way an animal’s body works changes when              Bear Research Project take blood and fat                                                                                    Meanwhile, neonatologist              nerve cells.”                             was kept cool for 72 hours and then
     it hibernates, however, and preparations             tissue samples from an anaesthetised                                                                                     Marianne Thoresen at the University         The scientists have spent more than    his brain was slowly re-warmed. After




                                                                                                                                                                     ole frobert
     start months in advance.                             hibernating bear for analysis.                                                                                           of Bristol in England and anaesthetist   10 years developing the technique,        seven days he was doing well and able
        When there is no fruit on the                                                                                                                                              John Dingley at Swansea University’s     and Riley became the first in the world   to take milk for the first time.




                                                                                                                                          ole frobert
     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                                                                                                               FINDING THE ANSWER is risky. Bears                     “These animals eat seeds, ‘good’ fats,             Cholesterol-defying arteries are not the
     blood–brain barrier and fuel the brain                                                                                                             are dangerous animals. Even when                       unsaturated vegetable fats and they also        only evolutionary trick scientists are trying
     and the rest of the organs,” Andrews                                                                                                               hibernating, they can wake suddenly and                do a good job of producing omega-3 and          to understand. Colorado State University
     says. “The switch-over of metabolism                                                                                                               attack unwanted visitors. So scientists use            omega-6 fats, which have beneficial effects     biomedical engineer Seth Donahue studies
     to use fat instead of carbohydrates as                                                                                                             radio transmitters or GPS devices to locate            on cardiovascular systems.”                     how hibernators preserve muscle tone and
     primary fuel for the body is the main                                                                                                              previously tagged bears in the wilds of                  It’s not only the hibernators’ diet that’s    bone strength despite several months of
     task of hibernators.”                                                                                                                              Sweden, and tranquilise the animals with               desaturated. They are also pretty good at       inactivity each year.
        As with most biological processes,                                                                                                              darts before approaching. Then, they take              desaturating the fats in their bodies.             People normally lose bone as they age.
     hibernation is directed by the products                                                                                                            blood samples and fat                                                                                                          Studies have shown
     of genes, specifically enzymes. Two
     enzymes, PDK4 and PTL, are partially
                                                                                                                                                        tissue biopsies. Artery
                                                                                                                                                        samples are collected
                                                                                                                                                                                               “There is some kind of connection between                                               that after menopause,
                                                                                                                                                                                                                                                                                       women lose 1 to 2%
     responsible for the fuel switch that                                                                                                               from bears killed during           hibernators and human survivors, people who have                                            of their bone mineral
     is seen in hibernating animals, as                                                                                                                 the legal hunting season.                                                                                                      density per year.
     first described by Andrews and his                                                                                                                    “We have found that             cheated death after being submerged in icy water,                                           Bedridden patients
     colleagues in a 1998 research article                                                                                                              the levels of ‘good’ and                                                                                                       may lose 3 to 4%
     published in the Proceedings of the                                                                                                                ‘bad’ cholesterol are both            or buried in snow, without oxygen, for hours.”                                           of their skeletal
     National Academy of Sciences. PDK4             Breath samples are
                                                                                                                                                        increased in bears’ blood.                                                                                                     mass each month.
     stops carbohydrate metabolism in               collected to characterise                                                                           This may have some protective effect,”                   “If fats are saturated they will solidify,    Hibernators, on the other hand, wake up
     order to preserve the glucose that             brown bear metabolism.                                                                              Fröbert says. In his team’s experiment,                turn into butter at low body temperatures”      from their long-term dormancy with their
     animals have stored from their last                                                                                                                published online in Clinical and Translational         so the animals could not use them,              skeletons and muscles unaffected. In the
     meal. PTL is responsible for starting up                                                                                                           Science in January 2012, it’s not clear how            says Andrews. “But being unsaturated            case of the squirrels, they have no option
     the mechanism to convert fat into usable         double its body weight by adding fat during    attack or a stroke,” explains Ole Fröbert,         the animals keep their arteries flexible.              they stay liquid even in a very cold            if they want to avoid being eaten by foxes
     energy at low body temperatures.                 summer and autumn.                             a cardiologist from Örebro University              Researchers hope to find a molecule that               environment.” How they do it is what he         and panthers – they have to stay strong
        Consuming 0.2–0.3% of their body mass           “The cholesterol levels in their blood       Hospital in Sweden. “However, brown bears          could similarly affect humans’ blood vessels.          and other researchers want to understand.       and mobile and have developed the genetic
     per day, hibernators can survive until           are double that of humans and their heart      do not suffer any of this.”                           The secret may be in the animals’ diet.             “Hibernators selectively use fat all winter     ability to do this.
     spring. And the bigger their fat stores, the     beats very, very slowly which is also a risk     How bears keep their arteries safe under         “The fat that hibernators use is very                  long and, despite the extra pounds, they           Monitoring bone metabolism markers
     greater their chances of getting through         factor for blood clotting. These conditions    these conditions is what Fröbert and his           different from the fat humans consume –                stay healthy. This could help us combat         in the blood of five bears, Donahue found
     the winter – for example, a bear is able to      [would] put a person on the verge of a heart   colleagues are investigating.                      we often eat saturated fats,” says Andrews.            obesity and diabetes in humans.”                that “during hibernation, bone loss and          >>



     78	   www.cosmosmagazine.com 	                                                                                                   Cosmos 46         Cosmos 46	                                                                                                              www.cosmosmagazine.com	   79
istoCk
               bone breakdown do happen but bears have          they were injected with either human
>>

               developed the biological mechanism to            or bear PTH and had their bone density
               [keep] bone production constant”. In a 2008      measured and compared over several weeks.




                                                                                                                                        getty
               review published in the American Journal         Bones became stronger in the rats that




                                                                                                                                                                                                                                                    wikimedia




                                                                                                                                                                                                                                                                                                         wikimedia
               of Physiology, he and his colleagues found       had received the bear PTH. These results
               this is due to the high levels of two chemical   might lead to more effective treatments for
               compounds, osteocalcin and parathyroid           osteoporosis in post-menopausal women,
               hormone, or PTH.                                 who are susceptible to bone loss.
                  “Just as in humans, bear                                               Another hibernating
               bones release minerals                                                 animal that has caught
               during periods of inactivity.         “Scientists in                   scientists’ attention
               But instead of excreting                                               is the arctic ground
                                                  Pittsburgh revived




                                                                                                                                                                      wikimedia
               calcium, PTH induces its re-                                           squirrel, Spermophilus
               absorption by the kidneys
               and puts it back in bears’
                                                   dogs after three                   parryii. From early
                                                                                      September to late April
                                                   hours of clinical




                                                                                                                                                                                                                                                                                                                                 getty
               skeletons,” Donahue says.                                              this small, orange and
               “Osteocalcin is a protein                                              white squirrel cools
               normally excreted in the         death – no heartbeat,                 its body to a core
               urine. Since bears do not                                              temperature of -2.9ºC,
                                                 no breathing and no




                                                                                                                                                                                                                                                                getty
                                                                                                                           wikimedia
               urinate during hibernation,                                            which is the lowest
               osteocalcin levels increase                                            known naturally
               and contribute to bone               brain activity.”                  occurring temperature
               mineralisation and                                                     in mammals. At the
               building.”                                       same time, however, it keeps its brain,




                                                                                                                                                                      wikimedia
                                                                and other parts of the body involved
               HUMAN PARATHYROID hormone may                    in regulating and maintaining energy
               not be as efficient as bears’ at recycling       metabolism, above zero.




                                                                                                                                                                                                                                                                        jill zamzow
               minerals back into bones. Donahue and his          As Andrews explains, these are
               team are currently studying the hormone’s        physiological feats that non-hibernating
               bone-sparing power. “We have sequenced           animals, including humans, could never
               the gene for bear PTH, and used it to            survive. “A human will go hypothermic in                                                                          their muscles. Females wake long                                                                    known to aestivate, the heatwave equivalent
               produce a synthetic form of bear PTH             [temperatures] around 32ºC. The chemical                                                                          enough to birth cubs and lick                                                                       of winter hibernation – holes up in tree
               and reverse bone loss in rodent models of        reactions in our bodies just can’t take place,”     Animals around the                                            them clean before resuming their                           European hedgehog                        trunks in groups of four to five. Surviving
               osteoporosis,” says Donahue.                     he says. Yet the cunning arctic ground                                                                            slumber, while the cubs remain                              Scientific name Erinaceus               on fat stored in its tail, the fat-tailed dwarf
                 Donohue’s team used rats with surgically       squirrel is not only able to cool and heat          world have evolved                                            awake, suckling their mother and                            europaeus                               lemur becomes dormant to combat drought,
               removed ovaries, which simulates                 up its body each year – during hibernation,                                                                       waiting for spring.                                        Location Western Europe                  its body temperature varying with the
               menopause, making their bones develop            every week or so, the squirrel stirs, shivers       ingenious ways to survive                                                                                              Hibernates for 5–7 months                  outside temperature – reaching up to 30°C.
               osteoporosis and become spongy. Next,            without waking, re-warms to 37ºC for about          environmental extremes,                                       Red-eared slider                                     These hedgehogs build nests in which
                                                                                                                                                                                  Scientific name Trachemys scripta                to hibernate when the temperature drops            Black rockcod
                                                                                             Bears’ bodies
                                                                                                                    reports Ola Jachtorowicz.                                     elegans                                          below 16°C. While hibernating, they will still     Scientific name Notothenia coriiceps
                                                                                             continue to produce                                                                  Location Southern U.S.                           bristle (erect their spines) when touched or       Location Ocean around Antarctica
                                                                                             bone (shown here)      Common poorwill                                               Brumates for 6–7 months                          exposed to noise.                                  Hibernates for 6–8 months
                                                                                             during hibernation.
                                                                                                                    Scientific name Phalaenoptilus nuttali                        Called sliders for their ability to quickly                                                         In 2008, it became the first fish identified
                                                                                             Instead of excreting
                                                                                             minerals released      Location Western North America                                evade predators by slipping off rocks            Northern bat                                       to change its metabolic activity as part of an
                                                                                             from bones as          Hibernates for up to 3 months                                 and logs and into the water, these turtles       Scientific name Eptesicus nilssonii                annual cycle, becoming 20 times less active.
                                                                                             would normally         The only bird known to hibernate, the                         brumate (a reptilian version of hibernation)     Location Northern Europe to Japan                  Its dormancy pattern isn’t due to water
                                                                                             happen during a
                                                                                                                    poorwill doesn’t build a nest but sits in piles               through winter at the bottoms of ponds and       Hibernates for 4–8 months                          temperature, but most likely to lack of light
                                                                                             period of non-
                                                                                             activity, the bears’   of rocks or clumps of grass, concealed by its                 shallow lakes, occasionally rising for air.      Groups of two to four choose underground           during Antarctica’s long winter. It waits out
                                                                                             bodies instead         camouflage plumage. The Native American                                                                        spaces such as caves, mines, cellars               the darkness before resuming hunting prey.
                                                                                             re-absorb them         Hopi people called it Hölchoko or ‘the                        Monito del monte                                 and bunkers. They can hibernate in
                                                                                             into the kidneys
                                                                                             with the help of
                                                                                                                    sleeping one’.                                                Scientific name Dromiciops gliroides             conditions below 0°C, which benefits them          Mountain pygmy possum
                                                                                             two chemical                                                                         Location South America                           energetically and enables them to hibernate        Scientific name Burramys parvus
                                                                                             compounds.             American black bear                                           Hibernates for up to 4 months                    for up to eight months in a row.                   Location Australia
                                                                                             Research into this     Scientific name Ursus americanus                              A living fossil, the monito del monte (‘little                                                      Hibernates for 5–7 months
                                                                                             process could lead
                                                                                                                    Location North America                                        mountain monkey’) is ancestral to Australian     Fat-tailed dwarf lemur                             The critically endangered pygmy possum
SETH Donahue




                                                                                             to breakthroughs
                                                                                             in the treatment       Hibernates for 5–8 months                                     marsupials. It spends its life in trees and      Scientific name Cheirogaleus medius                burrows deep into snow and boulder crevices
                                                                                             of osteoporosis in     Considered highly efficient hibernators or                    bamboos of Andean temperate rainforests,         Location Madagascar                                in winter. Native to Australia’s alpine regions
                                                                                             humans.                ‘super-hibernators’, black bears recycle their                hibernating in well-hidden, spherical, water-    Aestivates for 6–8 months                          and only 11cm long, it is the country’s only
                                                                                                                    waste into proteins, which become part of                     resistant nests lined with moss or grass.        This primate – the only tropical mammal            hibernating marsupial.
                                                                                                                                                                                                                                                                                                                                                  >>



               80	   www.cosmosmagazine.com 	                                                                                                         Cosmos 46                   Cosmos 46	                                                                                                           www.cosmosmagazine.com	           81
12–20 hours, then goes into hibernation                                                                                                                     no heartbeat, no breathing and no brain         molecules that can damage proteins and              just 15 minutes this way,” adds Tisherman.
>>

     again without any tissue damage.                                                                                                                            activity. While Roth’s team focusses            DNA and lead to cell death, contributing to         A heart–lung bypass machine will be used to
                                                                                                                                                                 on slowing the metabolic rate and the           tissue damage or organ failure.                     restore blood circulation and oxygenation as
     SCIENTISTS HAVE identified several                                                                                                                          temperature comes down as a by-product,            Later in 2012, surgeon Samuel Tisherman          part of the resuscitation process.
     compounds that may explain how this is                                                                                                                      Kochanek’s team cooled the body in order        and his team, also at Safar Centre in                  Extreme cooling therapy – expanding
     possible. Andrews has found that PDK4                                                                                                                       to slow down the metabolic rate. They           Pittsburgh, will start a clinical trial to see if   across hospitals even before scientists
     and PTL, the same enzymes that switch                                                                                                                       drained the dogs’ blood and replaced            they can rescue patients who have suffered          and doctors completely understand how
     over metabolism, help cardiac physiology to                                                                                                                 it with a solution of low-temperature           cardiac arrest due to massive bleeding, by          it works – could also help treat some type
     work at low temperatures. “PTL is a protein                                                                                                                 glucose, dissolved oxygen and saline. The       chilling them to nearly 10°C.                       of poisonings, for which blood circulation
     produced in the human pancreas but we                                                                                                                       dogs came back to life after a blood                                                                       must be stopped. The power of
     have found it in the squirrels’ heart. The                                                                                                                  transfusion and an electric shock           “These are physiological feats                                 H2S to induce hypothermia is also
     reason is that it works very well in the cold.                                                                                                              to the heart, though a few suffered                                                                        being tested in patients with acute
     It can burn fat in the cold and allow the                                                                                                                   minor brain damage. Using a similar       that humans could never survive.”                                lung injury, multiple organ failure
     heart to continue beating.”                                                                                                                                 approach, a group of trauma surgeons                                                                       and some inflammatory diseases.
        In 2007, Tom Scanlan, a biologist now                                                                                                                    at Massachusetts General Hospital in              “Most of the time people with severe              However, failure to reproduce the effects
     at Oregon Health and Science University                                                                                                                     Boston reported successful results in several   trauma and blood loss don’t survive,” says          seen in mice in larger animals (such as
     in Portland, Oregon, published research                                                                                                                     experiments with Yorkshire pigs.                Tisherman. “Rapid cooling might be able to          sheep), as well as safety concerns, mean
     in Stroke describing how a derivative of                                                                                                                                                                    sustain the patient, particularly the brain,        further research is needed.
                                                      ole frobert




     thyroxine, a thyroid hormone, rapidly                                                                                                                       THE NEXT STEP IS to test suspended              long enough to buy time for surgeons to                Andrews remains optimistic. “In the
     lowers body temperature and slows heart                                                                                                                     animation in humans. When a person has          find the source of blood loss, repair the           future maybe we will have the ability to
     rate when injected into rodents. Six to eight                                                                                                               severe trauma and massive blood loss,           wound and restore heartbeat.”                       create transgenic hibernators, as we now
     hours after injection, they resumed normal                                                                                                                  oxygen supply also falls. When deprived           In the trial, body temperature will be            create transgenic mice, to better understand
     core body temperature and behaviour. The         Some bears can double their body weight during summer in preparation for winter hibernation.               of oxygen, an average person suffers brain      lowered by administering up to 20 litres of         how hibernation works.”
     team has produced several similar synthetic                                                                                                                 damage within five minutes and dies 15          cold fluid through a large tube placed into
     substances that show the same or even            survival was a result of a cold-induced state          humans, it enables core temperature to stay         minutes later. But restoring blood flow is      the aorta, the largest artery in the body.          Zuberoa Marcos is a Barcelona-based science writer and
     more potent induction of hypothermia.            similar to hibernation, as the mountain                uniform regardless of whether we are in the         dangerous too. The influx of oxygen-rich        “In the preclinical studies we have done in         scientific director of a weekly TV magazine at the Spanish
     Meanwhile, in 2006 in Nature, Cheng Chi          temperature dropped as low as 10ºC.                    Arctic or the Caribbean.                            blood produces so-called reactive oxygen        animals, we have cooled down the body in            Broadcasting Corporation.
     Lee, a molecular biologist at the University       “I am convinced there is some kind                     At his lab at the Fred Hutchinson Cancer
     of Texas in Houston, with his colleagues         of connection between hibernators and                  Research Centre in Seattle, Washington,
     showed that the 5’-AMP (five-prime               human survivors, people who have cheated               Roth placed mice inside tanks from which
     adenosine monophosphate) molecule also           death after being submerged in icy water, or           nearly all of the oxygen had been removed
     lowers mice’s core body temperature and          buried in snow, without oxygen, for hours,”            and made them breathe 80 parts per
     makes animals enter hibernation.                 says Andrews.                                          million of H2S. Their core body temperature
        Five-prime AMP is part                                                                                           plunged 20°C within minutes,
     of a cellular process called
     oxidative phosphorylation,
                                       The spin-off is a deeper understanding of                                         their heart rate declined more
                                                                                                                         than 50% and their metabolic
     which is the body’s power-       controversial medical technologies that can                                        rate tumbled. The animals stayed
     generating apparatus.                                                                                               in suspended animation for up
     Cells need oxygen to make         slow patients’ respiration to almost zero –                                       to six hours before the oxygen
     adenosine triphosphate,                                                                                             supply was turned back on.
     or ATP, the primary fuel            and bring them back from near death.                                            Surprisingly, they woke up with
     of life. As the organism’s                                                                                          no brain damage.
     body cools, it needs less oxygen, oxidative                                                               H2S seems to slow, or even stop, oxidative
     phosphorylation slows down or stops,             A lack of oxygen often kills people                    phosphorylation, the process by which
     and the animal simply rests. This process        who have had a cardiac arrest or a stroke.             cells produce energy. Roth’s experiment
     happens not only in mice, but also in            About five years ago, doctors began to                 showed that mice can survive when
     squirrels and other hibernating mammals.         experiment with therapies to cool down,                exposed to low oxygen concentrations that
     Perhaps even in humans.                          even temporarily, such patients’ bodies and            would otherwise be lethal to them. He is
        In October 2006, the first known case         reduce their need for oxygen. The results              also one of a number of researchers who
     of a human going into ‘hibernation’ was          have been nothing short of extraordinary.              are investigating the use of suspended
     described. After slipping and breaking his         In 2005, biochemist Mark Roth made                   animation in radical medical therapies.
     pelvis, a 35-year-old hiker survived 24          headline news worldwide when Science                     In February 2008, anaesthetist
     days in a mountain forest without food           published his team’s results showing                   Patrick Kochanek of the Safar Centre for
     or water. Mitsutaka Uchikoshi was found          that exposing mice to tiny doses of                    Resuscitation Research at the University
     unconscious on Rokko Mountain in Japan,          hydrogen sulphide – H2S – induced a state              of Pittsburgh at Titusville, Pennsylvania,
     with a body temperature close to 22ºC. He        of reversible hibernation. H2S is a foul-              and his colleagues published a paper in
     had a weak pulse and was suffering blood         smelling, corrosive, flammable and deadly              the Journal of Cerebral Blood Flow and
     loss. After referral to a hospital, he made      gas, produced naturally in tiny amounts in             Metabolism describing how he had revived
     a full recovery. His physicians believed his     the bodies of humans and other animals. In             dogs after three hours of clinical death –

     82	   www.cosmosmagazine.com 	                                                                                                                  Cosmos 46

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Total Shutdown

  • 1. 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 getty/iSTOCK scientists think that the genetic hardware required to go into hibernation is common Studying the physiology of hibernating bears offers insights that may among all mammals. So why is it that some help treat people with such illnesses as diabetes and osteoporosis. species hibernate and some do not? >> 76 www.cosmosmagazine.com Cosmos 46 Cosmos 46 www.cosmosmagazine.com 77
  • 2. A technique of cooling the brain There is an evolutionary explanation for >> is helping this, says Andrews. “Humans are largely a newborns at istock tropical species. We evolved in the tropics risk to avoid permanent where food is generally available. We have brain damage. very thin skin because we had little need to protect ourselves from the cold. If we GROUND SQUIRRELS can teach us School of Medicine in Wales have Nerve cell had evolved in Siberia or Northern Canada a lot about brain regeneration. In developed a pioneering technique endings in the brains we might have [developed] an ability to 2006, H. Craig Heller, a biologist to save the lives of babies at risk of of ground hibernate because we would be subjected to at Stanford University in the U.S., brain damage. Riley Joyce was born squirrels a limited growing season.” and his colleagues reported in The in April 2010 at the Royal United change during wikimedia Since the late 1800s, scientists have Journal of Neuroscience that during Hospital, Bath, without a pulse and hibernation. tried unsuccessfully to unlock the inner hibernation, squirrel brains retract not breathing, and with a 50% chance workings of hibernation. Yet molecular many of their dendrites, the tendril- of permanent brain injury. He was biology is slowly unravelling the mysteries like nerve-cell endings that receive transferred to St Michael’s Hospital, of this phenomenon. The spin-off is a information from other neurons. Yet Bristol, where Dingley used cooling deeper understanding of controversial each time the squirrels wake, even and xenon gas to safeguard his brain. upon whom it was tested. First, a cold medical technologies that can slow patients’ for only a few hours, the dendrites “Xenon is a very rare and chemically cap slowly cooled his head. Then a respiration to almost zero – and bring them regrow… and even faster than during inert gas found in tiny quantities in xenon breathing system, working in back from near death. embryonic development. Dendrite the air that we breathe,” explains conjunction with a mechanical lung retraction also occurs in humans Thoresen. “In lab studies we have ventilator, administered xenon into EVERY ANIMAL ON EARTH burns as we age, so understanding how seen it doubles the protective effect the lungs where it is absorbed into the fuel to get the energy to walk, breathe, squirrels regenerate their dendrites of cooling on the brain because it bloodstream, via which it reaches the sleep and keep their bodies at optimal might help develop new therapies for blocks a cell surface receptor whose brain. The xenon was administered temperatures. Nearly everything about the Scientists from the Scandinavian Brown damaged brains. activation can lead to the death of until Riley’s brain reached 33.5°C. He way an animal’s body works changes when Bear Research Project take blood and fat Meanwhile, neonatologist nerve cells.” was kept cool for 72 hours and then it hibernates, however, and preparations tissue samples from an anaesthetised Marianne Thoresen at the University The scientists have spent more than his brain was slowly re-warmed. After ole frobert start months in advance. hibernating bear for analysis. of Bristol in England and anaesthetist 10 years developing the technique, seven days he was doing well and able When there is no fruit on the John Dingley at Swansea University’s and Riley became the first in the world to take milk for the first time. ole frobert 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 FINDING THE ANSWER is risky. Bears “These animals eat seeds, ‘good’ fats, Cholesterol-defying arteries are not the blood–brain barrier and fuel the brain are dangerous animals. Even when unsaturated vegetable fats and they also only evolutionary trick scientists are trying and the rest of the organs,” Andrews hibernating, they can wake suddenly and do a good job of producing omega-3 and to understand. Colorado State University says. “The switch-over of metabolism attack unwanted visitors. So scientists use omega-6 fats, which have beneficial effects biomedical engineer Seth Donahue studies to use fat instead of carbohydrates as radio transmitters or GPS devices to locate on cardiovascular systems.” how hibernators preserve muscle tone and primary fuel for the body is the main previously tagged bears in the wilds of It’s not only the hibernators’ diet that’s bone strength despite several months of task of hibernators.” Sweden, and tranquilise the animals with desaturated. They are also pretty good at inactivity each year. As with most biological processes, darts before approaching. Then, they take desaturating the fats in their bodies. People normally lose bone as they age. hibernation is directed by the products blood samples and fat Studies have shown of genes, specifically enzymes. Two enzymes, PDK4 and PTL, are partially tissue biopsies. Artery samples are collected “There is some kind of connection between that after menopause, women lose 1 to 2% responsible for the fuel switch that from bears killed during hibernators and human survivors, people who have of their bone mineral is seen in hibernating animals, as the legal hunting season. density per year. first described by Andrews and his “We have found that cheated death after being submerged in icy water, Bedridden patients colleagues in a 1998 research article the levels of ‘good’ and may lose 3 to 4% published in the Proceedings of the ‘bad’ cholesterol are both or buried in snow, without oxygen, for hours.” of their skeletal National Academy of Sciences. PDK4 Breath samples are increased in bears’ blood. mass each month. stops carbohydrate metabolism in collected to characterise This may have some protective effect,” “If fats are saturated they will solidify, Hibernators, on the other hand, wake up order to preserve the glucose that brown bear metabolism. Fröbert says. In his team’s experiment, turn into butter at low body temperatures” from their long-term dormancy with their animals have stored from their last published online in Clinical and Translational so the animals could not use them, skeletons and muscles unaffected. In the meal. PTL is responsible for starting up Science in January 2012, it’s not clear how says Andrews. “But being unsaturated case of the squirrels, they have no option the mechanism to convert fat into usable double its body weight by adding fat during attack or a stroke,” explains Ole Fröbert, the animals keep their arteries flexible. they stay liquid even in a very cold if they want to avoid being eaten by foxes energy at low body temperatures. summer and autumn. a cardiologist from Örebro University Researchers hope to find a molecule that environment.” How they do it is what he and panthers – they have to stay strong Consuming 0.2–0.3% of their body mass “The cholesterol levels in their blood Hospital in Sweden. “However, brown bears could similarly affect humans’ blood vessels. and other researchers want to understand. and mobile and have developed the genetic per day, hibernators can survive until are double that of humans and their heart do not suffer any of this.” The secret may be in the animals’ diet. “Hibernators selectively use fat all winter ability to do this. spring. And the bigger their fat stores, the beats very, very slowly which is also a risk How bears keep their arteries safe under “The fat that hibernators use is very long and, despite the extra pounds, they Monitoring bone metabolism markers greater their chances of getting through factor for blood clotting. These conditions these conditions is what Fröbert and his different from the fat humans consume – stay healthy. This could help us combat in the blood of five bears, Donahue found the winter – for example, a bear is able to [would] put a person on the verge of a heart colleagues are investigating. we often eat saturated fats,” says Andrews. obesity and diabetes in humans.” that “during hibernation, bone loss and >> 78 www.cosmosmagazine.com Cosmos 46 Cosmos 46 www.cosmosmagazine.com 79
  • 3. istoCk bone breakdown do happen but bears have they were injected with either human >> developed the biological mechanism to or bear PTH and had their bone density [keep] bone production constant”. In a 2008 measured and compared over several weeks. getty review published in the American Journal Bones became stronger in the rats that wikimedia wikimedia of Physiology, he and his colleagues found had received the bear PTH. These results this is due to the high levels of two chemical might lead to more effective treatments for compounds, osteocalcin and parathyroid osteoporosis in post-menopausal women, hormone, or PTH. who are susceptible to bone loss. “Just as in humans, bear Another hibernating bones release minerals animal that has caught during periods of inactivity. “Scientists in scientists’ attention But instead of excreting is the arctic ground Pittsburgh revived wikimedia calcium, PTH induces its re- squirrel, Spermophilus absorption by the kidneys and puts it back in bears’ dogs after three parryii. From early September to late April hours of clinical getty skeletons,” Donahue says. this small, orange and “Osteocalcin is a protein white squirrel cools normally excreted in the death – no heartbeat, its body to a core urine. Since bears do not temperature of -2.9ºC, no breathing and no getty wikimedia urinate during hibernation, which is the lowest osteocalcin levels increase known naturally and contribute to bone brain activity.” occurring temperature mineralisation and in mammals. At the building.” same time, however, it keeps its brain, wikimedia and other parts of the body involved HUMAN PARATHYROID hormone may in regulating and maintaining energy not be as efficient as bears’ at recycling metabolism, above zero. jill zamzow minerals back into bones. Donahue and his As Andrews explains, these are team are currently studying the hormone’s physiological feats that non-hibernating bone-sparing power. “We have sequenced animals, including humans, could never the gene for bear PTH, and used it to survive. “A human will go hypothermic in their muscles. Females wake long known to aestivate, the heatwave equivalent produce a synthetic form of bear PTH [temperatures] around 32ºC. The chemical enough to birth cubs and lick of winter hibernation – holes up in tree and reverse bone loss in rodent models of reactions in our bodies just can’t take place,” Animals around the them clean before resuming their European hedgehog trunks in groups of four to five. Surviving osteoporosis,” says Donahue. he says. Yet the cunning arctic ground slumber, while the cubs remain Scientific name Erinaceus on fat stored in its tail, the fat-tailed dwarf Donohue’s team used rats with surgically squirrel is not only able to cool and heat world have evolved awake, suckling their mother and europaeus lemur becomes dormant to combat drought, removed ovaries, which simulates up its body each year – during hibernation, waiting for spring. Location Western Europe its body temperature varying with the menopause, making their bones develop every week or so, the squirrel stirs, shivers ingenious ways to survive Hibernates for 5–7 months outside temperature – reaching up to 30°C. osteoporosis and become spongy. Next, without waking, re-warms to 37ºC for about environmental extremes, Red-eared slider These hedgehogs build nests in which Scientific name Trachemys scripta to hibernate when the temperature drops Black rockcod Bears’ bodies reports Ola Jachtorowicz. elegans below 16°C. While hibernating, they will still Scientific name Notothenia coriiceps continue to produce Location Southern U.S. bristle (erect their spines) when touched or Location Ocean around Antarctica bone (shown here) Common poorwill Brumates for 6–7 months exposed to noise. Hibernates for 6–8 months during hibernation. Scientific name Phalaenoptilus nuttali Called sliders for their ability to quickly In 2008, it became the first fish identified Instead of excreting minerals released Location Western North America evade predators by slipping off rocks Northern bat to change its metabolic activity as part of an from bones as Hibernates for up to 3 months and logs and into the water, these turtles Scientific name Eptesicus nilssonii annual cycle, becoming 20 times less active. would normally The only bird known to hibernate, the brumate (a reptilian version of hibernation) Location Northern Europe to Japan Its dormancy pattern isn’t due to water happen during a poorwill doesn’t build a nest but sits in piles through winter at the bottoms of ponds and Hibernates for 4–8 months temperature, but most likely to lack of light period of non- activity, the bears’ of rocks or clumps of grass, concealed by its shallow lakes, occasionally rising for air. Groups of two to four choose underground during Antarctica’s long winter. It waits out bodies instead camouflage plumage. The Native American spaces such as caves, mines, cellars the darkness before resuming hunting prey. re-absorb them Hopi people called it Hölchoko or ‘the Monito del monte and bunkers. They can hibernate in into the kidneys with the help of sleeping one’. Scientific name Dromiciops gliroides conditions below 0°C, which benefits them Mountain pygmy possum two chemical Location South America energetically and enables them to hibernate Scientific name Burramys parvus compounds. American black bear Hibernates for up to 4 months for up to eight months in a row. Location Australia Research into this Scientific name Ursus americanus A living fossil, the monito del monte (‘little Hibernates for 5–7 months process could lead Location North America mountain monkey’) is ancestral to Australian Fat-tailed dwarf lemur The critically endangered pygmy possum SETH Donahue to breakthroughs in the treatment Hibernates for 5–8 months marsupials. It spends its life in trees and Scientific name Cheirogaleus medius burrows deep into snow and boulder crevices of osteoporosis in Considered highly efficient hibernators or bamboos of Andean temperate rainforests, Location Madagascar in winter. Native to Australia’s alpine regions humans. ‘super-hibernators’, black bears recycle their hibernating in well-hidden, spherical, water- Aestivates for 6–8 months and only 11cm long, it is the country’s only waste into proteins, which become part of resistant nests lined with moss or grass. This primate – the only tropical mammal hibernating marsupial. >> 80 www.cosmosmagazine.com Cosmos 46 Cosmos 46 www.cosmosmagazine.com 81
  • 4. 12–20 hours, then goes into hibernation no heartbeat, no breathing and no brain molecules that can damage proteins and just 15 minutes this way,” adds Tisherman. >> again without any tissue damage. activity. While Roth’s team focusses DNA and lead to cell death, contributing to A heart–lung bypass machine will be used to on slowing the metabolic rate and the tissue damage or organ failure. restore blood circulation and oxygenation as SCIENTISTS HAVE identified several temperature comes down as a by-product, Later in 2012, surgeon Samuel Tisherman part of the resuscitation process. compounds that may explain how this is Kochanek’s team cooled the body in order and his team, also at Safar Centre in Extreme cooling therapy – expanding possible. Andrews has found that PDK4 to slow down the metabolic rate. They Pittsburgh, will start a clinical trial to see if across hospitals even before scientists and PTL, the same enzymes that switch drained the dogs’ blood and replaced they can rescue patients who have suffered and doctors completely understand how over metabolism, help cardiac physiology to it with a solution of low-temperature cardiac arrest due to massive bleeding, by it works – could also help treat some type work at low temperatures. “PTL is a protein glucose, dissolved oxygen and saline. The chilling them to nearly 10°C. of poisonings, for which blood circulation produced in the human pancreas but we dogs came back to life after a blood must be stopped. The power of have found it in the squirrels’ heart. The transfusion and an electric shock “These are physiological feats H2S to induce hypothermia is also reason is that it works very well in the cold. to the heart, though a few suffered being tested in patients with acute It can burn fat in the cold and allow the minor brain damage. Using a similar that humans could never survive.” lung injury, multiple organ failure heart to continue beating.” approach, a group of trauma surgeons and some inflammatory diseases. In 2007, Tom Scanlan, a biologist now at Massachusetts General Hospital in “Most of the time people with severe However, failure to reproduce the effects at Oregon Health and Science University Boston reported successful results in several trauma and blood loss don’t survive,” says seen in mice in larger animals (such as in Portland, Oregon, published research experiments with Yorkshire pigs. Tisherman. “Rapid cooling might be able to sheep), as well as safety concerns, mean in Stroke describing how a derivative of sustain the patient, particularly the brain, further research is needed. ole frobert thyroxine, a thyroid hormone, rapidly THE NEXT STEP IS to test suspended long enough to buy time for surgeons to Andrews remains optimistic. “In the lowers body temperature and slows heart animation in humans. When a person has find the source of blood loss, repair the future maybe we will have the ability to rate when injected into rodents. Six to eight severe trauma and massive blood loss, wound and restore heartbeat.” create transgenic hibernators, as we now hours after injection, they resumed normal oxygen supply also falls. When deprived In the trial, body temperature will be create transgenic mice, to better understand core body temperature and behaviour. The Some bears can double their body weight during summer in preparation for winter hibernation. of oxygen, an average person suffers brain lowered by administering up to 20 litres of how hibernation works.” team has produced several similar synthetic damage within five minutes and dies 15 cold fluid through a large tube placed into substances that show the same or even survival was a result of a cold-induced state humans, it enables core temperature to stay minutes later. But restoring blood flow is the aorta, the largest artery in the body. Zuberoa Marcos is a Barcelona-based science writer and more potent induction of hypothermia. similar to hibernation, as the mountain uniform regardless of whether we are in the dangerous too. The influx of oxygen-rich “In the preclinical studies we have done in scientific director of a weekly TV magazine at the Spanish Meanwhile, in 2006 in Nature, Cheng Chi temperature dropped as low as 10ºC. Arctic or the Caribbean. blood produces so-called reactive oxygen animals, we have cooled down the body in Broadcasting Corporation. Lee, a molecular biologist at the University “I am convinced there is some kind At his lab at the Fred Hutchinson Cancer of Texas in Houston, with his colleagues of connection between hibernators and Research Centre in Seattle, Washington, showed that the 5’-AMP (five-prime human survivors, people who have cheated Roth placed mice inside tanks from which adenosine monophosphate) molecule also death after being submerged in icy water, or nearly all of the oxygen had been removed lowers mice’s core body temperature and buried in snow, without oxygen, for hours,” and made them breathe 80 parts per makes animals enter hibernation. says Andrews. million of H2S. Their core body temperature Five-prime AMP is part plunged 20°C within minutes, of a cellular process called oxidative phosphorylation, The spin-off is a deeper understanding of their heart rate declined more than 50% and their metabolic which is the body’s power- controversial medical technologies that can rate tumbled. The animals stayed generating apparatus. in suspended animation for up Cells need oxygen to make slow patients’ respiration to almost zero – to six hours before the oxygen adenosine triphosphate, supply was turned back on. or ATP, the primary fuel and bring them back from near death. Surprisingly, they woke up with of life. As the organism’s no brain damage. body cools, it needs less oxygen, oxidative H2S seems to slow, or even stop, oxidative phosphorylation slows down or stops, A lack of oxygen often kills people phosphorylation, the process by which and the animal simply rests. This process who have had a cardiac arrest or a stroke. cells produce energy. Roth’s experiment happens not only in mice, but also in About five years ago, doctors began to showed that mice can survive when squirrels and other hibernating mammals. experiment with therapies to cool down, exposed to low oxygen concentrations that Perhaps even in humans. even temporarily, such patients’ bodies and would otherwise be lethal to them. He is In October 2006, the first known case reduce their need for oxygen. The results also one of a number of researchers who of a human going into ‘hibernation’ was have been nothing short of extraordinary. are investigating the use of suspended described. After slipping and breaking his In 2005, biochemist Mark Roth made animation in radical medical therapies. pelvis, a 35-year-old hiker survived 24 headline news worldwide when Science In February 2008, anaesthetist days in a mountain forest without food published his team’s results showing Patrick Kochanek of the Safar Centre for or water. Mitsutaka Uchikoshi was found that exposing mice to tiny doses of Resuscitation Research at the University unconscious on Rokko Mountain in Japan, hydrogen sulphide – H2S – induced a state of Pittsburgh at Titusville, Pennsylvania, with a body temperature close to 22ºC. He of reversible hibernation. H2S is a foul- and his colleagues published a paper in had a weak pulse and was suffering blood smelling, corrosive, flammable and deadly the Journal of Cerebral Blood Flow and loss. After referral to a hospital, he made gas, produced naturally in tiny amounts in Metabolism describing how he had revived a full recovery. His physicians believed his the bodies of humans and other animals. In dogs after three hours of clinical death – 82 www.cosmosmagazine.com Cosmos 46