Hibernation: Deeeeeeep sleeeeeeeep

 


1. Chillin' out

2. Cold trance or transplant?

3. Stroke of luck

4. Waking, meeting, sleeping, mating

Alyssa Anderson, 7, smiles at her grandmother, Sandra Mambrino, in Hartford, Conn., Feb. 19, 2003, after Mambrino received a kidney transplant. Mambrino had been scheduled for a transplant on Feb. 17, but a snowstorm prevented the kidney's delivery. The transplant team found another kidney and performed a successful transplant. Better organ storage techniques could prevent transplant organs from going to waste. AP Photo/Bob Child

 

13-line ground squirrel hibernates.

big-cheeked rodent stands on hind legs, eating
If you think hibernation is optional, talk to the arctic squirrel. Spending the winter underground, with the metabolism largely shut down, is key to the survival of many mammals living near the poles. Photo: U.S. Department of Interior.

Hibernation breaks all the rules


Organ transplants: Use it or lose it
You can hardly blame biologists for their hibernation fixation. Hibernation, after all, breaks all the rules. Cool a human adult below 20 degrees Celsius, and you'd cause death by cardiac arrest -- heart attack.blonde woman in hospital bed holds hand of young girl in striped shirt In any case, body cells would gradually leak, inciting a deadly inundation of injurious ions.

But to hibernating mammals, including ground squirrels, marmots and bears, such temperatures are all in a year's work. Why?

While a number of human cadavers, supposedly including former baseball great Ted Williams, subsist in high-rent cold storage, the study of hibernation is not about rich people who haven't finished bugging the rest of us. Instead, many researchers hope to pull medical wonders, like protecting the brain against stroke or preserving organs for transplant, from the hibernators' bag of biological tricks.

On the average day, 63 Americans get an organ transplant, but another 16 die waiting for a heart, lung or liver. The deaths are caused by a shortage of donors -- and a shortage of time. Unless genetic testing, transportation and transplantation can happen fast -- in six hours or less for a heart transplant -- the organ may spoil.

Livers, which serve the body as a biochemical reactor, breaking down waste products and producing a variety of essential chemicals, last a bit longer, but after 24 hours, cells start to die. After 36 hours they are largely useless.

Although a shortage of blood causes some damage to organs that await transplantation in tubs and vats, much of the damage actually occurs when the blood supply is restored. (This "reperfusion" injury also affects the brain after a stroke.)

But hibernators are immune to injury at both the cooling and warming ends of the spectrum, says Carey. "When animals go into hibernation, they go into a kind of natural cold-storage state." Although they do have a limited blood supply, "the body temperature is very similar to the one used to store human organs, around 4 degrees Celsius."

striped squirrel rolled up in the shape of a ball

High liver
To understand the changes, Carey and her colleagues, including James Southard, from the UW-Madison department of surgery, and Sandy Martin, from the University of Colorado Health Sciences Center in Denver, are comparing livers in rats, a non-hibernator, with ground squirrels that are either active or hibernating. Rat livers, she says, decline as fast as human livers, but the livers of hibernators last much longer, even if removed in summer, while the animals are active.

But the champion survivalist, she says, is the liver taken from a torpid hibernator, which survives unscathed much longer than livers from summer ground squirrels or rats.

One physiological phenomenon (take a mouthful of peanut butter and repeat THAT three times!) that damages would-be transplant organs is an immune cell called the Kupffer cell. "Often immune cells sense reperfusion as some kind of danger," Carey explains. "They become over-activated, and are primed to release free radicals and other toxic substances," starting a series of inflammatory processes. It's all rather normal -- these are how Kupffer cells do their job -- assassinating bacteria -- Carey says, "but in this case they are doing it to their own tissue."

blonde woman in maroon fleece talks and gestures When a rat liver is cold-stored for 24 hours and the blood supply is restored, she says, "you see activation of the Kupffer cells. When we do this to a hibernator's liver, even if it's been stored twice as long, we see minimal activation of Kupffer cells."

Researcher Hannah Carey studies a flock (squad, crew, herd, gang, gaggle) of 13-lined ground squirrels. One goal: figure out how they survive the cold, and whether that could help preserve organs before transplant. Carey's shown in the UW-Madison Biotron, a climate-controlled research center.

Taken out of circulation
Organ death is actually cell death, but exactly which cells are dying? In the liver, Carey says, the dear departed are often blood vessel cells rather than specialized liver cells. The liver lacks the capillaries found in other tissues. But its blood passages, like capillaries, are lined with endothelial cells, which are, Carey says, "quite vulnerable to stress." Once they die, liver cells are cut off from the blood supply, and they, in turn, kick the bucket. "We've seen this endothelial cell death in rat livers after reperfusion," says Carey. "So we did the same exact experiment in hibernators, and the degree of cell death was greatly reduced."

Several other mechanisms may account for the super survival of a hibernator's liver.

Less of the poetically named inflammatory protein, NF-kB, which is released in a rat's liver after 24 hours of storage.

More of the active form of the antioxidant glutathione.

More of the protective protein, HSP70, a "heat shock" protein that protects stressed cells from damage.

We hate to burden you with all this chemistry, but keep your eyes on the prize. While hibernators probably use many mechanisms to survive cold storage and rewarming, learning to use just one or two could keep organs alive longer, allowing surgeons to find the best transplant recipient.

Still uncertain is how the new knowledge will be used, says Carey. "The goal is to come up with a pharmacological way to manipulate the human liver to be more similar to the hibernator's liver, for example, to dampen the inappropriate immune response and preserve the antioxidants." In other words, it may be possible to add chemicals to the "UW Solution" now used to store transplant organs.

striped, furry back shows through small animal bedding at the bottom of a cage
In these cold, dark cages, hibernating 13-lined ground squirrels happily pass the winter. Strangely, they will start hibernating even without signals from the environment.

An alternative tactic would attempt to initiate a vestigial genetic program for hibernation. That may seem farfetched, but consider this: It's not just ground squirrels and marmots that hibernate. Indeed, says Carey, who has studied hibernation for 23 years, all but one of the main lineages of mammals contain at least one species with the ability to enter torpor and survive to tell the tale. (Among primates, that would be one species of lemur, Carey says).

Translated: The genes required for hibernation are probably present in the average caffeine-addicted night owl. And if they can be activated, perhaps it would be easier to transplant healthy organs.

Stroke: It's another condition where reperfusion injury kills the brain.

 

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