This could be a problem, because a medical future that includes DADLEing is not as improbable as it might seem. Think about it: DADLE seems to protect squirrels from the vagaries of cold, malnutrition, and wide swings in blood pressure and heart rate. Maybe, then, it could work the same magic on humans who are trauma victims or surgical patients?
Some of the earliest hints that DADLE and hibernation could be protective come from experiments that were conducted around the same time that Dawe created his mandatory blood donor program for squirrels. Dr. John Willis, a biologist, was curious about how squirrels’ cells continue to function under conditions that really shouldn’t support life. In particular, he was interested in their cell membranes.
Willis knew that it takes a lot of energy to maintain the proper gradients of electrolytes inside and outside cells. As we saw in chapter 3 in Dr. Becker’s class, the pumps in a cell’s membrane need to keep running constantly to make sure that sodium, for instance, stays outside the cell, and potassium, for instance, stays inside. But how well are these energy-intensive pumps maintained during the low-metabolic state of hibernation?
To find out, Willis gathered a group of unsuspecting ground squirrels and hamsters and let them hibernate. Then they were killed, Willis adds in a Professor-Plum-in-the-library-with-a-candlestick rhetorical flourish, “by a blow on the head.” Willis then proceeded to chop the squirrels up into tiny pieces.
The hamsters, the report continues, remained awake after the ground squirrels had gone to sleep. This is, of course, very reasonable behavior for any thoughtful hamster who has learned that his squirrel cousins have just been felled by blows to the head, and then minced. But there’s no arguing with Mother Nature, and the hamsters, too, eventually went into hibernation. Then they were also converted, immediately and perfunctorily, to rodent mulch.
Once that had been accomplished, Willis found that the gradients across the animals’ cells were preserved even in the deepest hibernation. Somehow, even with their metabolism reduced to a tiny fraction of normal, the squirrels’ and hamsters’ cells continued to maintain themselves at the concentrations to which they’d become accustomed. So the decline in metabolism that hamsters and squirrels undergo seems to spare these essential cellular functions.
That’s very interesting, because remember from chapter 3 that one of the chief causes of injury when cells go without oxygen is a failure of their membranes to maintain the proper gradients. Sodium flows in, potassium flows out, and the cell dies. Willis’s experiment suggests the possibility that hibernation might stabilize cell membranes, protecting us from the damage that results from a loss of oxygen.
But how might that work? And how might DADLE be involved? To answer that question, we need to take a quick refresher course in cellular physiology.
THELMA AND LOUISE TAKE A ROAD TRIP
As I clawed my way through basic science courses in medical school, I had to memorize dozens of obscure enzyme names. In a desperate effort to keep them all organized in my head, I placed them into two camps. In the social circle of cellular enzymes, it seemed to me, there are some that tend to nudge a cell toward survival and others that are ready to give up when things get difficult.
You can think of these, as I did, as either Thelma or Louise enzymes, from the film of that name. One group (Louise, at least at the beginning of the film) is upbeat, confident, and always up for the next challenge. But the other (Thelma, though not at the end) is moping and doom-saying and generally not much fun to be around.
There’s one enzyme in particular, known as p53, which is one of these Thelma enzymes. It has several constructive functions, such as fixing broken DNA. But if its repair efforts are unsuccessful, p53 simply throws its hands in the air and gives up. That is, it nudges a cell toward a graceful exit.
Where this story gets interesting is how in hibernation the balance of power shifts. Conservative (Thelma) enzymes become less influential. Instead, they’re replaced by more relaxed (Louise) enzymes.
In a hibernating squirrel, the conservative p53 (Thelma) enzyme drops to approximately one-fourth the concentration found in awake summer squirrels. In contrast, other so-called anti-apoptotic enzymes (Louise enzymes) take over. These are known as anti-apoptotic enzymes because they prevent cell death (apoptosis), and cells produce more of these enzymes during hibernation. Anti-apoptotic enzymes, which go by awkward names like Bcl-XL and Akt, have the general effect of preserving cell function and preventing cells from dying.
So you’ve got Thelma enzymes and Louise enzymes on a road trip together. Normally, the Thelma enzymes are in control. They get to choose when and where to stop, and they keep the radio tuned rigidly to the local NPR station. But gradually those Thelma enzymes become more flexible, open-minded, and cheerful. They loosen up. They start having fun. And they let Louise flip the radio to R&B, for a change.
What’s really interesting is that some animals may be able to enjoy the benefits of this shift in enzymes without actually hibernating. All of the fun of a road trip without leaving the driveway. That is, just the ability to hibernate seems to protect cells against hypoxia—the state of being oxygen-deprived.
Some studies have found that even if an animal is awake and alert, as long as it’s capable of hibernating, it may be better able to survive the rigors of hypoxia during surgery. Most of these experiments were done on—you guessed it—squirrels. Researchers took wide-awake squirrels and subjected them to conditions of hypoxia. Then the researchers euthanized them and removed their livers to examine under a microscope and test those liver cells’ ability to function. In these experiments, the squirrels’ livers did exceptionally well. At least, they did as well as a squirrel liver can do when it’s extracted from the squirrel in which it’s been living happily, and placed unceremoniously into a freezer. Even those livers that had until recently been part of a wide-awake squirrel did better than expected when they were frozen. Their mitochondria worked better, for instance. And they produced more bile, and their cells were more viable. (The newly liverless squirrels, though, not so much.)
This is fascinating because it suggests that there may be protective genes in some animals that can be activated by stress. That is, animals may have genes that get switched on very quickly when bad things happen to them, or to their livers. So it’s not only the state of hibernation that’s protective, but maybe there’s a capacity for self-protection that kicks in—or can be made to kick in—when animals aren’t hibernating.
This, in turn, leads us to another interesting possibility. Maybe DADLE can protect organs even when those organs come from animals who don’t hibernate. Maybe DADLEing could be therapeutic.
In one fascinating study, researchers removed the hearts of a bunch of rabbits. Usually, the removal of a heart marks the gruesome end of an experiment rather than its beginning. In fact, I think it’s safe to say that most organs, once they’re no longer connected to the body they’ve grown up with, will figure out that they no longer have a purpose. They will then cease doing whatever it is they’re supposed to be doing.
But a rabbit heart, it turns out, is not particularly perceptive. Detached from its rabbit body, a rabbit heart just keeps going . . . and going . . . and going . . . as the famous tagline says. So it’s possible to study rabbit hearts that are out on their own, separated from their respective rabbits.
In this experiment, researchers removed the rabbit hearts and, as a consolation prize, perfused them with a solution that supplied enough oxygen and nutrients to keep them beating. Some of these lonely hearts were flooded with DADLE. Others got the serum (blood minus the red blood cells) from hibernating woodchucks or bears.
What happened? All of the hearts given DADLE functioned better—two times better, in fact—than the other hearts. They contracted with more force, and were able to pump more efficiently. In fact, they were almost normal. That is, except for the rather obvious fact that they were not connected to a
rabbit.
So all of this research raised hopes that DADLE—or something similar—might be able to protect the organs of rabbits and rats from injury when they’re without oxygen. But what’s most exciting about all of this research is the possibility that there might be something out there that could confer some of the protective effects of hibernation in species that don’t hibernate—like humans. That possibility might help to explain Mitsutaka Uchikoshi’s amazing survival. And more important, it might help to save other lives in the future.
THE RISE AND FALL OF THE “FRENCH COCKTAIL”
Before we think about how we might induce humans to hibernate, we need to think about another, much more basic, question: Why should we bother? Why might human hibernation be a good thing?
Well, as we’ve seen, hibernation might be a nifty aid to space travel, of course. But there aren’t many people who are thinking seriously about that. So I admit that the need for hibernation to reach Mars is not exactly pressing.
However, lots of researchers are thinking very, very seriously about how the tricks of hibernation might be used to help patients. Some researchers think that maybe, someday, hibernation might also be a routine part of clinical care.
The theory—which we’ve heard before from resuscitation researchers—is that when there isn’t much oxygen available, brains and other organs do better if they use less. When the oxygen supply is limited, as it is in the setting of cardiac arrest or major trauma, a brain that needs less oxygen is going to be more likely to wake up. And when it does, it’s going to be more likely to retain its ability to control basic functions like walking, talking, and thinking.
As the science of resuscitation has shown us, the quickest way to convince a brain to use less oxygen is to cool it. As a very rough rule of thumb, the brain’s metabolic rate decreases by about 6 percent for every 1 degree Celsius drop from a normal 37 degrees. So if you can get a person’s core temperature down to 29 degrees, you will have cut his metabolism almost in half. And at 20 degrees, it will be at only 10 percent of normal. So, the logic goes, if we can reduce oxygen requirements this much, it means that people will be able to survive longer under difficult conditions.
Cooling a person who is undergoing CPR isn’t so difficult, because that person is dead. Of course there are physics-related challenges, as we’ve seen. But the person’s body is not actively resisting efforts to cool it, for instance, by shivering. And—let’s face it—if you go a little overboard it’s no big deal because that person is, again, no longer alive.
Hibernation, though, is a whole different ball game. To induce hibernation in people who are not yet dead, you need to cool them while their bodies are fighting back. That is, you need to overcome the body’s natural inclination to stay warm. That’s an enormous challenge.
The term “artificial hibernation” was first used in 1905, long before we understood much about the mechanisms of hibernation. But it wasn’t until the 1950s that science began to make some progress and researchers began to figure out how to cool living people without turning them into dead people.
At the forefront of this movement was Dr. Henri Laborit, a Parisian surgeon with a craggy, leonine face who appears in photographs of the day dangling an elegant cigarette. Laborit was a little obsessed by the Romantic notion that the body can’t fight two battles at once. The challenges of maintaining body temperature, he said, compete with the need to fight insults like hypotension and infection. So he came up with the idea of a mix of drugs that would convince the body that temperature regulation wasn’t so important after all, allowing it to focus on other things, like staying alive.
This concoction became known as the French Cocktail. Alas, this cocktail is not nearly as much fun as it sounds. Instead of happy-making ingredients like brandy, Champagne, and absinthe, its ingredients were far more prosaic. One was promethazine, which is an antihistamine that is sold today under the brand name Phenergan as an antinausea drug. Another was diethazine, an anticholinergic drug that used to be prescribed for Parkinson’s disease, but now isn’t used for much of anything.
In fact, it’s a little hard to figure out exactly what went into the French Cocktail. The French apparently approached the science of artificial hibernation in much the same way they tackled winemaking. Perhaps subscribing to the terroir theory of drug development, there were multiple versions of the cocktail, each containing as many as six or seven ingredients that varied from hospital to hospital. So it’s difficult to tell what those patients were getting.
It’s also difficult to figure out whether the French Cocktail improved surgical mortality rates. People weren’t keeping reliable records, and reports aren’t available. Moreover, even sparse anecdotes and case reports are hard to make sense of, again because patients got many different drugs, in unique combinations, at varying doses.
TAKE ONE GROIN AND APPLY ICE (LOTS OF IT)
Perhaps not surprisingly, given the lack of standardization as well as suspicions of laissez-faire science, the ascendancy of the French Cocktail proved to be short-lived. Soon, pointed questions arose (mostly from across the channel) about its scientific legitimacy. It’s at this point that the cutting edge of artificial hibernation research moved to the United Kingdom, where less eloquent minds took over naming responsibilities.
Leading this charge was the Irish anesthesiologist Dr. John Wharry Dundee, who embraced wholeheartedly the value of a reduced metabolism. “So obvious are the advantages of a state of affairs wherein the cellular oxygen requirements are markedly reduced,” he says in an influential paper, “that they need not be further discussed.” Well, so there then.
Where he and others disagreed with the French, though, was about the value of all the drugs that the French loved so ardently. Dundee argued that the cocktail itself could only be expected to have a modest direct effect on temperature. That is, he didn’t think that the cocktail was really cooling people. However, he suggested, if a patient were cooled with ice, drugs might prevent the body from rewarming itself.
Thus he took issue with the initial description of “artificial hibernation,” and suggested that this phrase, which had been coming into vogue, was inaccurate. None of the changes induced in the operating room, he said, are physiologically the same, nor are they as profound, as those experienced in the wild. Instead, he began to refer to the process of lowering a patient’s temperature and metabolism during surgery as “induced hypothermia with autonomic block.” Alas, that hardly sounds like something you’d want to wear your best pearls for, and it doesn’t even make for a good acronym.
Faced with this onslaught of science, logic, and boring names, the French Cocktail really never had a chance. It fell out of favor in operating rooms and was replaced by the British “lytic cocktail,” which is a step down, nomenclature-wise, if you ask me. (“Lytic,” in this case, refers to the ability of drugs to block the autonomic nervous system’s natural response to hypothermia.)
Dundee’s cocktail was simple, and sported only three key ingredients. Trust the Brits to take all the fun out of experimentation. Those three were promethazine, pethidine, and chlorpromazine. Promethazine, remember, is the antihistamine that made an appearance in the short-lived French Cocktail. Pethidine is better known in the United States as meperidine, an opioid that is sold under the brand name Demerol. It’s a mild analgesic but has the unique property of reducing shivering responses. Chlorpromazine is a dopamine antagonist that was one of the earliest drugs used for schizophrenia, and is still marketed under the name Thorazine.
The purpose of that lytic cocktail was not to induce artificial hibernation but to prevent the shivering response that a healthy body exhibits when it realizes that it’s getting close to room temperature. Meanwhile, if you really wanted to induce a state of suspended animation—although Dundee didn’t use that term—you needed to cool the body. The solution, he proposed, was ice. Lots of it.
In 1953, Dundee and his co
lleagues reported their success with a series of twenty-six patients who received the lytic cocktail, along with enough ice to chill a couple kegs of beer. First, patients were given the lytic cocktail, and the dose was repeated if the patient showed signs of shivering. What comes next, though, is enough to make me very happy that I didn’t need surgery back in 1953.
“Ice bags were first placed on the groin,” the report says with admirable British nonchalance. Next, “in the absence of a response” to the ice-on-the-groin maneuver, the body was covered in ice.
Frankly, the absence of a response to a bucketful of ice dumped onto one’s exposed groin seems highly unlikely. At least, in anyone who is not already very, very dead. That’s British stoicism for you.
But there’s more. Dundee’s report mentions, as an aside, that no anesthesia was used in these procedures. This, it seems, was a period in which being a patient of Dr. Dundee’s was probably only marginally more pleasant than being a donor ground squirrel.
Granted, no one was slicing these patients open and taking blood from their aortas, and all of them truly needed surgery. Nevertheless, they underwent a variety of invasive procedures that today would involve nerve blocks and general anesthesia. For instance, out of twenty-six unlucky bodies, surgeons removed one colon, one breast, two thyroids, two spleens, three bladders, and five stomachs. (Actually, it was three stomachs and two partial stomachs. I rounded up.)
All of this, mind you, without the comforts of anesthesia. And yet, because of the combination of the lytic cocktail and cold (plus perhaps a healthy desire to get the hell out of there), these patients don’t appear to have protested. Much.
Using this procedure, Dundee reports proudly that only five patients died, which isn’t a bad mortality rate for that time. He also says that temperatures during these procedures sometimes dropped an average of 3.2 degrees, to 32 degrees Celsius.
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