The surprising promise of inducing torpor

Inducing torpor and hibernation in humans could improve survival rates for heart attack and violence victims. It might also be the key to long distance space travel.

Take fluffy the cat. Found inert and apparently lifeless in a snow drift during the deep freeze in Montana last US winter, she resembled a trashed shag pile carpet on arrival at the Kalispell Animal Clinic. Her temperature didn’t register.

Only hours later, however, gentle rewarming elicited a growl and Fluffy was discharged in full feline health. She was likely in a state loosely called “suspended animation”. Body temperature plunges and metabolism slows to a point where the need for oxygen is so low that, even without breathing, vital organs such as the brain come out unscathed. It happens in humans, too.

In 2006, Australian mountaineer Lincoln Hall was pronounced dead by sherpas on Mount Everest after showing no signs of life for two hours. Despite a full night at 8800 metres with no oxygen, he was found next morning alive, if disoriented, by a fellow climber. These feats have not gone unnoticed by scientists.

Researchers are trialling extreme cooling to “buy time” for surgeons to fix patients whose hearts have stopped after a shooting or stabbing. Others are hunting the switch that hibernating animals use to put cell systems on hold, sometimes for years, when resources are scarce. There is intense interest, too, from space agencies hoping “human hibernation” could solve the problems of prolonged space flight. It is on Earth, however, that the need is most pressing. 

Sam Tisherman is a trauma surgeon whose patch, the Shock Trauma Centre at the University of Maryland Medical Centre in Baltimore, is a stone’s throw from the gritty housing projects whose drug-fuelled violence was depicted in the HBO series The Wire. His entree into trauma research more than 30 years ago was spurred by something seemingly innocuous, however.

“All we knew is that the patient was involved in some sort of altercation, supposedly an argument about something related to bowling shoes,” he says. “But he got stabbed in the heart … we actually got him to the operating room, but he kept arresting and we couldn’t resuscitate him.”

The incident firmed Tisherman’s resolve to study how cooling might give surgeons time to sew up a punctured heart or blood vessel without their patient ending up with brain damage from lack of oxygen.

His initial work in dogs in the early 1990s had dramatic results. “Our animal model was that we would bleed them to the point of cardiac arrest, and then we would cool them down and leave them in cardiac arrest for a period of time,” he says.

One dog, he recalls, was an American coonhound. Its heart stopped for a full hour, but it recovered completely, and a lab technician took it home as a pet.

These days Tisherman’s main research is on humans, and it could well change the way trauma is managed.

He heads up a trial called Emergency Preservation and Resuscitation for Cardiac Arrest from Trauma (EPR-CAT), which is slated for completion in December. It offers a chance at life to victims of penetrating trauma, including stabbing and gunshot wounds, who bleed to the point where their heart stops.

Survival rates for these conditions are notoriously low – between 2 and 5%.

In a logistical feat, surgeons open the patient’s chest and pump upwards of 40 litres of iced saline into the aorta to chill the body down to 10 degrees Celsius. As they repair the damage, a second team connects the patient to a heart bypass machine, which pumps in oxygen-rich blood as the patient is warmed back up.

The study’s conclusion is pending and Tisherman won’t talk about results. There is reason to think, however, that he may be up against it. Cooling research has been on something of a roller coaster in recent years and someone intimately familiar with the ride is Stephen Bernard.

I’ve come to meet Bernard at the Alfred Hospital in Melbourne, Australia, where he works as an intensive care physician.

He walks me through the Emergency and Trauma Centre to one of the three “pods” of the intensive care unit that looks after heart patients. An air ambulance has just landed on the adjacent helipad.

Bernard exudes calm amid the quiet tension of beeping monitors and prostrate patients; being unconscious is a typical entry requirement.

His understated demeanour belies the fact that in 2002 he almost single-handedly changed the treatment of people whose hearts stop, outside of hospital, after a heart attack.

He led a study that found if you cooled those people by piling ice packs on and around them, nearly half survived to discharge from hospital. Of those not put on ice, only a quarter made it home. This study sparked a tectonic shift in cardiac arrest treatment. “Therapeutic hypothermia” was the order of the day.

A photo from the era shows a patient, presumably retrieved from a supermarket, buried under packets of frozen chips.

All of that came crashing down in 2013, however, when a much larger study found cooled cardiac arrest patients died at the same rate as those kept at normal temperature. Bernard changed tack, instead infusing iced saline into the veins of cardiac arrest victims.

They did worse.

“There was a general acceptance around the world from the correspondence we got that, yep, that’s established that pretty definitively. We won’t be doing that,” he says.

Local paramedics no longer chill patients after cardiac arrest, but Bernard, who is also medical director of Ambulance Victoria, maintains faith in the power of cool.

He says the problem for heart patients may not be the cold itself, but how you make it happen. “The idea of taking your average 80 kilo human, who is going to be 60 litres of water, and lowering them, over say five minutes, from 36 degrees to 33 degrees, the physics of that is simply daunting,” he says.

Infusing litres of iced saline into someone having chest compressions, Bernard explains, could make it harder to generate the pressure gradient needed to move blood around the body.

So, does this bode ill for Tisherman?

Not necessarily. His patients have bled litres, making “space” to infuse the icy fluids. He also suctions the saline from an incision in the heart and has a heart-lung machine take over, all of which makes pumping in big volumes workable. 

The challenges, nonetheless, make a simpler approach tantalising. “The dream of being able to inject something that slows everything down,” is how Bernard phrases it.

As it happens, dream fulfilment could well come in the guise of hibernation research. 

Fritz Geiser is Professor of Zoology at the University of New England in New South Wales, Australia. He studies hibernation and its shorter version, “daily torpor”, which lasts less than 24 hours. In these states, animals drop energy expenditure and reduce their metabolic rate to as low as 5% of normal. Body temperature plummets by between 10 and 35 degrees Celsius.

Torpor, Geiser tells me, is more common that you might think. 

“We did an estimate that 40% or so of terrestrial animals do it in Australia,” he says. One such animal is the echidna, for which, Geiser explains, it isn’t just winter chill but bushfires that trigger torpor.

“Echidnas go from 32 to four or five degrees body temperature. Really low,” he says, adding that it’s adaptive for echidnas to be inanimate after fires because food is scarce and they won’t need as much. And with ground cover lost they become sitting ducks for predators, hence the value of hiding out in a burrow.

But how, precisely, is torpor triggered?

“If you expose animals to smoke and charcoal they increase torpor. So somehow it’s a stick which tells them watch out,” says Geiser.

“We don’t know the neural signal, and we also don’t understand what the trigger is for switching on torpor.”

Unsurprisingly, there are plenty of people who want to find that out.

Among them is Craig Franklin, Professor of Zoology at the University of Queensland. Franklin studies an Australian animal with an extreme knack for withstanding the Big Dry that so often parches the outback.

“Frogs that live in the desert and burrow underground remain in a state of dormancy called aestivation that can last for years at a time. They don’t feed, drink or move,” he says.

“There’re instances when there’s been no rain, there’s been a drought period for three or four years, it rains, and the frogs come out of nowhere.”

Franklin says if you put a frog in a jar in a cupboard it will go into aestivation. In those dark confines it can drop its oxygen consumption by as much as 80%. That’s impressive, but it has to go even lower for the frog to survive years without eating. The bush must have its own secret ingredient; in April, Franklin’s team began a hunt for it.

“The species that we work on burrows into this really thick clay, this black soil, that occurs in the Darling Downs. And one thing you notice when you dig into that, when it’s wet, is that it smells of hydrogen sulfide,” says Franklin.

His interest in hydrogen sulfide is understandable because, when it comes to lowering metabolism, rotten egg gas has form.

Hydrogen sulfide puts serious brakes on the process by which cells use oxygen to make the energy source adenosine triphosphate (ATP), something that happens in their powerhouse, the mitochondria.

Peter Radermacher, Professor of Anaesthesiology and Intensive Care Medicine at University Medical School in Ulm, Germany, has been studying hydrogen sulfide for more than a decade. He has at his disposal a very special facility.

“We would probably be a unique institution in Europe that has a rodent as well as large animal experimental intensive care unit,” he says.

In 2010, in that ICU for animals, Radermacher did a study that blocked blood flow to the kidneys of pigs for 90 minutes. Animals that got hydrogen sulfide ended up with less kidney damage.

The hydrogen sulfide probably protected the kidneys, in part, by reducing harmful by-products of oxygen metabolism. Which sounds good, but Radermacher says that effect teeters on a razor’s edge.

“The difference between a manipulation as you like to have it, on the one hand, and poisonous irreversible damage, is extremely narrow,” he says.

In short, there is a fine line between a hydrogen sulfide dose that puts mitochondrial power generation on a go-slow, and one that blows up the plant altogether. 

So Radermacher switched tack, looking for an existing drug with a clear safety profile that also liberates hydrogen sulfide. He may have a promising candidate. Apart from its use in gold mining and water treatment, sodium thiosulfate also happens to be one of the antidotes for human cyanide poisoning.

In research presented in March, Radermacher’s team treated a special kind of pig with sodium thiosulphate. The animals had a genetic mutation that lowers the availability of innate hydrogen sulphide.

Mimicking the bleeding of trauma, they also had 30% of their blood volume drained.

The thiosulphate pigs had significantly less lung damage than controls, suggesting the drug protects against a lack of oxygen from low blood flow.

“Thiosulphate was promising, I must admit that I was surprised,” says Radermacher, whose research is partly funded by the German Ministry of Defence. He is a doctor with the German Navy, and shortly after we speak he is scheduled to drop beneath the waves with a team of submariners.

What, then, of the potential for thiosulphate to help humans – injured service personnel, for example?

“One could imagine that, if there is no logistical hindrance, you could treat haemorrhaged soldiers in the battlefield using that molecule in the idea to buy time for definite management,” says Radermacher.

He is, however, quick to temper expectations.

“This is really speculative and for the future. It is certainly not for next year.”

If Radermacher is focused on the theatre of war, other researchers are looking to the stars. 

Matteo Cerri is a physiologist at the University of Bologna and a consultant to the European Space Agency. He might also have discovered the hibernation switch.

In 2013 he did an experiment that took aim at the brainstem of rats. It’s a region that harbours the very stuff of life, the central control room for breathing and heartbeat. Cerri’s focus, however, was on a bean-shaped group of neurons at its lower end called the raphe pallidus.

“When you activate this area, metabolism goes high and body temperature increases, heart rate increases. It’s like when you have a fever,” he says.

“This brainstem region looked like that could be the spot where you could turn off metabolism. And so I said, well, let’s try.”

Try he did. Those rats got a nanoinjection of muscimol, a drug that mimics the action of the brain’s chemical messenger gamma-aminobutyric acid (GABA), straight into the raphe pallidus. Over Skype, with a cheery Italian inflection and some serious understatement, Cerri tells me of the result.

“Surprisingly, it worked the first time.”

The rats underwent major drops in brain temperature and heart rate. And they became lethargic, all consistent with a state called “synthetic torpor”.

Cerri, however, has his eyes on a bigger prize, one involving people and faraway planets.

“Radiation is the number one problem for long-term space exploration,” he says, referring to what are commonly known as “cosmic rays”.

“If you fly to Mars you get a high dose of radiation, like very significant. It won’t kill you right away, but it is high. If you consider to fly beyond Mars, it is definitely going to kill you.”

Cerri explains that some hibernating animals are resistant to radiation damage, possibly because torpor slows cell division and enhances DNA repair. That’s a big reason why he wants to replicate synthetic torpor in humans.

He understands, though, that getting a brain surgeon to do injections into a human brainstem could be tricky – it’s the very definition of surgical tiger country. He has, therefore, explored a different brain region in experiments he is currently preparing for journal submission.

“We know there is a network of neurons in the hypothalamus that looks clearly to be specifically activated in torpor,” he says.

“I believe that they are elaborating the energetic status of the animal, like the brain calculates or computes the energy expenditure. And when the result of this computation is negative, when there is a negative energy balance, then torpor is triggered.”

Cerri tells me his data strongly support the idea that fasting triggers torpor in mice through an effect on the raphe pallidus via the hypothalamus.

The upshot is that he is chasing down existing drugs that could target the hypothalamus; he has a cocktail in mind that he hopes to trial in mice. And if it works, he tells me, it could one day solve another niggling challenge of long-distance space travel.

“Six people of the crew pretty much kept in what would be a studio apartment. Privacy issues are very high,” he says. “It would not be strange if somebody was flipping out.”

Cerri alerts me to a recent incident where a man stabbed a colleague at a remote Antarctic research station. Hibernation would certainly put paid to such bickering in space. Which shows the goals of trauma prevention and interplanetary travel are both well within the orbit of human hibernation research.

Contingent on the planets aligning, of course.