Hitting the pause button on life

If other members of the animal kingdom can shut down their bodies over winter, then why can't we?

 Illustration by  Cara Penton

Illustration by Cara Penton

It looks like a garden ornament forgotten outside over the winter. Half-hidden in the leaf litter of the boreal forest sit the remains of a frog, a victim of the unforgiving Canadian winter. A thin layer of ice and snow coats its muddy, mottled brown skin. Its heart has stopped beating, and its limbs are cold and brittle. Yet, remarkably, it isn’t over for this unfortunate little frog.

The inside of the frog’s cells are crammed with glucose, which acts as a natural antifreeze. Ice formation is strategically limited to areas where it is comparatively harmless, like the spaces outside cells. A sugar-laden frog can survive the freezing of about two-thirds of its body water over the winter. Warm spring weather will reanimate the frog, and it will live to hop another day.

The wood frog, Rana sylvatica, is one of many animals to master the art of a reversible, coma-like state known as metabolic depression. Metabolically depressed animals use tiny amounts of energy, sometimes so little that scientists can’t tell if they have any metabolism at all. Somehow, these animals press the pause button on life, outlasting hard times in demanding environments. Could humans ever learn to imitate death like these animals? Workers from fields as diverse as medicine to space exploration are itching to know the answer.

 
  The wood frog can survive becoming frozen during the bitter North American winter.   W-van/Wikimedia Commons  (CC BY 3.0)

The wood frog can survive becoming frozen during the bitter North American winter. W-van/Wikimedia Commons (CC BY 3.0)

 

Rana sylvatica isn’t even the only frog to go into suspended animation. Other species living in desert environments, like Spencer's burrowing frog from central Australia, will go dormant and bake themselves in the heat. They can spend months encased in a mucous cocoon, patiently waiting for the rains to bring them back to life. Some fish, like the African lungfish, use a very similar strategy during droughts.

Compared to frog popsicles and frog jerky, the seasonal hibernation of ground squirrels and other small mammals seems subtle and painless. They cosy up in dens and tree hollows, munching on food caches, and go for occasional walks to stretch their legs. While they keep breathing and don’t freeze, a hibernating ground squirrel still produces so little heat that it is cold to the touch.

Many other animals, including some not particularly renowned for surviving extreme environments, will go into a deep sleep state known as daily torpor, a less severe form of metabolic depression. Hummingbirds, for example, slip into torpor to bed down for the night. They cut their body temperature by half, and drop their heart rate from about 1200 beats per minute to fewer than 200. Still, hummingbirds seem to just scrape by most of the time, burning through huge amounts of fat and losing about 10% of their body weight per night. It’s no wonder that they wake up so very hungry.

Whether they are amphibians, mammals, birds, or something else, animals use metabolic depression to thrive in places where they otherwise have no business surviving. At northern latitudes, frozen ponds, streams, and lakes leave frogs with nothing to eat and nowhere to live during the winter. Similarly, small mammals have a difficult time finding food when most nuts and fruits are buried under inches of snow. For the hummingbird, daily torpor is the only way their life in the fast lane happens at all – they use so many calories just to stay alive that they must drastically reduce their metabolism to take a nap without starving to death.

 
  To preserve their energy reserves, hummingbirds go into a state of torpor every night.   Kevin Bondelli/Wikimedia Commons  (CC BY-SA 3.0)

To preserve their energy reserves, hummingbirds go into a state of torpor every night. Kevin Bondelli/Wikimedia Commons (CC BY-SA 3.0)

 

Despite the huge variety of practitioners, there are some common themes in how animals reduce their metabolism. Radical changes in behaviour, physiology, and cellular biochemistry all work together to save as much energy as possible. Many animals go into “intentional hypothermia”, and this careful decrease in body temperature deepens energy savings by slowing down the chemical reactions occurring in cells. A slew of biochemical adjustments lock in the suspended animation. For example, many proteins are chemically deactivated so they do not waste precious resources or energy as heat.

Animals in metabolically depressed states are alive, but just barely. The great comparative physiologist Kjell Johansen called this “turning down the pilot light”: biological processes critical to survival, like preventing cells from swelling and exploding, slow to a crawl. Luxuries, like growth and reproduction, shut down completely.

Scientists want to know how each subtle change in biochemistry contributes to the creation of a metabolically depressed state. Cellular metabolic pathways are complicated and integrated, and alteration of a single protein can have unexpected, cascading effects. Perhaps the most intriguing lines of investigation to date are the recent advances in the metabolic control field. Under the right conditions, researchers can artificially induce metabolically depressed states in animals that do not naturally go into torpor, like mice and rats. Some groups have gone a step further, and restored normal metabolic rates without any lingering effects on brain function.

Synthetic torpor — also known as suspended animation, metabolic flexibility or “cryosleep” — sounds straight out of science-fiction movies like Interstellar, Aliens, and Star Trek. The reality of synthetic torpor is much less glamorous than gleaming chrome pods in the belly of a spaceship, being limited to Earthling research labs with little to no involvement of extra-terrestrials.

Current research is chasing the master switches and controllers of metabolism, focussing largely on the mitochondria and the central nervous system. The ultimate goal is to reverse engineer the sequence of events that induce a harmless, temporary coma. If successful, this research has a range of fantastical applications, including long-term space flight to Mars and slowing the progression of deadly diseases until modern medicine catches up with a cure.

 
  Inducing synthetic torpor in humans could become an essential technology in future Mars missions.   Les Bossinas, NASA Lewis Research Center/Wikimedia Commons  (public domain)

Inducing synthetic torpor in humans could become an essential technology in future Mars missions. Les Bossinas, NASA Lewis Research Center/Wikimedia Commons (public domain)

 

Mitochondria supply energy to cells, and so naturally catch the eye of researchers asking questions about how metabolism is controlled. Messing with the mitochondria’s ability to supply energy reduces metabolic rate, and some hibernators modify their mitochondrial physiology during torpor. This has led some research groups to try and control metabolism from the bottom up by regulating the amount of energy available for a cell to use.

One of the ways scientists can do this is by treating animals with hydrogen sulfide, a potent inhibitor of mitochondrial function, which seems to put mice into a state of reversible suspended animation without any lasting damage. While initially promising, attempts to scale up to non-mouse models, such as pigs and sheep, have so far been unsuccessful, and many basic questions remain unanswered. For example, scientists are not sure if hitting the mitochondria alone is enough to start the signalling cascade for sustainable metabolic depression.

Alternatively, some groups are trying to control metabolism from the top down through the brain’s thermoregulatory centre in the hypothalamus. Their strategy is to trick the brain into recognising a new, colder body temperature as “normal,” causing a controlled decrease in core body temperature similar to hibernators. One promising route is to activate A1 adenosine receptors with 6N-cyclohexyladenosine, a drug that induces torpor in small mammals when injected in a cold room. However, this “artificial hypothermia” lacks some of the hallmarks of natural metabolic depression, such as a severe decrease in heart rate and characteristic changes in gene expression.

The caveats of preliminary work into synthetic torpor have done little to stave off the imaginations of doctors, clinicians, and scientists tinkering with the biological machine. Piece by piece, we’re mapping out this machine’s blueprint — the on and off switches, the safety valves — using increasingly sophisticated molecular and biochemical tools. Perhaps soon we will learn to imitate death, and venture far beyond the human limits of healthcare, space exploration, and maybe even life as we know it.

Edited by Andrew Katsis