Cheating Death

by Sanjay Gupta

  What we desperately need, says Becker, is a reset button. “If you could reboot the system the way you reboot your computer, we should easily be able to save people. If we’re able to achieve that it would be one of the largest revolutions in emergency care, in any kind of care, that’s ever taken place.”

  * * *

  WHEN HE WAS just getting started as a scientist, you wouldn’t have pegged Mark Roth as the guy to defeat death. His father died when he was just seven years old. His mother was unable to support the family and left Roth and his six siblings to be raised in an orphanage in Hershey, Pennsylvania. 9 Life was hard but burning muscles and hungry lungs were a way out; Roth became a runner, fast enough to win a track scholarship at the University of Oregon, the hotbed of long-distance running back in the 1970s. His grades, though, weren’t great. “I was exhausted from running all the time,” he says. Roth managed a degree in biology, but when he took the entrance exam for medical school, his scores were so low he couldn’t get in anywhere. “I didn’t become a scientist out of any calling,” he told me. “I had no choice.”

  He plugged away in fields like molecular biology, getting a few NIH grants, doing a postdoc at Johns Hopkins, but nothing that seemed to break through. It didn’t bother him much, not until 1996, when something happened that changed his life.

  By then Roth had moved to Seattle, and started work at the Fred Hutchinson Cancer Research Center. He and his wife were raising a young daughter, and then they had another and nothing was the same again. Hannah, the baby, had Down syndrome and a laundry list of other problems. When she was a little over a year old, she went into the hospital and never came out again.

  It was only very recently that Roth has been willing to talk about the situation in public. When I asked if he thinks about his daughter every day, he told me, “It’s a bit like you’re driving across the country and you stop somewhere, and it’s like you never left. I mean, you’re still going on, but you’re still there. Part of you is still there. I don’t know how to put it otherwise.”

  Of course, I couldn’t help but wonder whether it was losing a child that inspired this man to seek a way to hold back death. It’s not so simple as all that, but then again, it’s not so far off the mark, either. Losing Hannah sent Roth into a deep round of soul-searching, and he came to the conclusion that he’d been wasting his time. “If you don’t want to lose your job, you become conservative, you keep your head down,” he told me. “And it’s pretty unfortunate, because without the willingness to fail, the possibility for great success is eliminated. When my daughter passed away, it occurred to me that I should play the game a little more risky. There would be a probability of failure but I shouldn’t worry about that. It’s okay.”

  Before he got into suspended animation, Roth had worked in genetics. Going way back, way before he lost a daughter, he had been interested in the science of living forever. The same way he used to take apart an alarm clock in his off-hours away from the lab, he thought about how immortality might work. “But it was like a hobby,” says Roth. “It wasn’t my job. My job was to do other things.”

  Losing Hannah gave him a sense of urgency. “I started to study this because I wanted to make a difference in my lifetime” is how he sums it up. “Do it now” became the mantra.

  And Roth told me something else that was really interesting: After all the pain, the sense of urgency felt good. It felt like freedom. “After that experience, I decided that the things that were more important to do were the things that I was actually not focused on, and I wasn’t focused on them because I was pretty much afraid of failing,” he says.

  And so a hobby became his life’s work. “I was very interested in the molecular basis of immortality. There’s a small subset of cells in your body, germ cells, which have the capacity to go on to the next generation. This is the germ line—what as far as we know are immortal cells that always beget offspring as far as we know forever,” said Roth. Germ cells go through a unique cycle that results in their becoming either an egg cell or sperm, depending on whether you’re a man or a woman. If you successfully reproduce, an actual piece of this germ cell will live on in your offspring. It goes on forever as long as your children have their own children, and so on.

  Another thing: egg cells have an interesting quality. They sit around for years without doing anything, and you can see the same phenomenon in other parts of the body. Your skin cells don’t do much unless you get a cut. Then they work overtime, growing together to patch the hole. This sitting around could be viewed, in a way, as suspended animation, or quiescence, to use a favorite term of Roth’s. For this next phase of his life—the making-a-difference phase—he decided to see if he could find a way to turn quiescence on and off.

  Roth likes movies, and his favorite is The Princess Bride. There’s a great scene where Westley, the hero played by Cary Elwes, is nearly tortured to death. To all appearances, he’s a goner. Fortunately, his friends track down the alchemist Miracle Max, played by Billy Crystal. “It just so happens that your friend here is only mostly dead,” Max reassures them. “There’s a big difference between mostly dead and all dead. Mostly dead is slightly alive… .” In a scene to inspire any devotee of suspended animation, Miracle Max goes on to feed Westley the antidote, allowing him to continue in pursuit of his true love, Buttercup.

  Roth says the scene comes to life in his laboratory. “The joke in my lab, when we’re doing this, is ‘Are they really dead?’ Well, it depends—how long did you wait? Just how dead were these animals? It’s kind of ridiculous, but you find yourself saying, ‘That’s not so dead. I can steal this piece of real estate from death.’ ”

  When it comes to the science, the work is all about manipulating oxygen. You see, the energy-producing part of each cell is like a candle slowly burning oxygen—fuel—and turning it into water. The air we breathe is about 21 percent oxygen. At a concentration of 6 to 8 percent, death from respiratory failure will come in less than ten minutes. The same effect takes place in the blood, when oxygen levels are not replenished by breathing. That launches the chemical cascade of death in every cell.

  Here is where Roth saw a loophole—a way to cheat death: those deadly chemical reactions require the presence of some oxygen. Curiosity led Roth to wonder what would happen if he subtracted that oxygen from the equation. His first experiments involved fruit flies and a type of small roundworm. He gassed them with carbon monoxide, which cells take up in place of oxygen, leaving no receptors to absorb the oxygen. (This is why carbon monoxide is deadly.) The thing is, without any oxygen at all the deadly chemical reactions couldn’t take place. Given a high dose of carbon monoxide, each insect froze in place, but it wasn’t dead. It was like hitting the pause button on the remote. Each insect could survive twenty-four hours, then resume its business as soon as the carbon monoxide in the enclosure was replaced by oxygen. 10

  After that, Roth turned his attention to the zebrafish. Zebrafish, like fruit flies and roundworms, are considered “model animals,” which means their biology and development are extremely well understood. Scientists study embryonic development in zebrafish because they develop from eggs into tiny fish larvae in just three days. The fish also develop outside the mother, making them easy to work with. Roth put a zebrafish embryo in a sealed bag, along with a chemical that essentially sucked all the oxygen out of the embryo’s body and converted it into water. Without oxygen, the embryo stopped growing. Its heart stopped beating, but it didn’t “die.” When Roth restored the oxygen a day later, the embryo picked up where it had left off. By day four—instead of day three—it was a baby zebrafish, indistinguishable from any other. 11

  Says Roth, “When you reduce oxygen levels to a certain point, you kill [the organism]. But when you reduce it one hundredfold past the point that kills them, they do fine.” When carbon monoxide took the place of oxygen in each cell, the damaging chemical reactions simply couldn’t take place. It made me think of smothering a fire—burning being another chemical r
eaction that requires oxygen.

  It was the same with roundworms. With an intermediate oxygen concentration—what Roth calls “evil oxygen tension”—they would suffer a version of reperfusion injury and die. But in an atmosphere of 0.1 percent oxygen, “there’s a state of suspended animation. And if you put them back into room air, they resume all their life processes as if it never happened,” said Roth.

  It was weird stuff. Stuff that seemed like it might fit better in the Science Fiction Museum, the roof of which is visible from the back window of Roth’s lab. Even now, he shakes his head with amazement: “We wait a week without doing anything, and then they just start going again. And we’re just… wow!”

  What does it mean to hit the pause button like that? “It sort of starts to get philosophical,” he says. “As far as we know, if you were this creature, you’d be here, and then you’d be here, and somebody would say, ‘You know, it’s no longer Sunday. It’s Tuesday, Bob.’ And you’d be like, ‘I don’t know that. For me, it’s just Sunday.’ ”

  After the worms and the flies and the zebrafish, Roth was ready to move up to mammals, but first he made a few changes. Inspired by a documentary about Mexican caves that contain hydrogen sulfide gas, Roth decided to use that compound in place of carbon monoxide. 12 Hydrogen sulfide has a near-identical action in the body and is equally deadly, but it clings less tightly to the body’s red blood cells. That makes it easier to reverse the suspended animation effect when the time is right. (For the same reason, it is easier to reverse a potentially deadly case of hydrogen sulfide poisoning than a case of carbon monoxide poisoning.) 13

  Roth had reason to think it would work. People who spend time around hydrogen sulfide—workers in paper mills, for example, or people who explore caves—-occasionally suffer what’s known as a knockdown. They get a whiff of the gas, and boom, they’re out. If they’re alone, it’s bad news. If someone happens to be nearby and sees the knockdown, and help arrives to pull the victim into fresh air—well, they snap out of it. No memory, but no problem. 14

  With the worms and the fish, it was real suspended animation. Roth had turned off the lights. With the mice, he would turn the dimmer down, but not all the way. There would still be a faint glow, sort of like turning off the stove but leaving the pilot light on to burn.

  In Roth’s lab, when he turned the dial, the hydrogen sulfide produced an immediate effect. The first mouse to get it saw its metabolism drop by half in just five minutes. Within six hours, it was about 10 percent of normal. The mouse was taking ten breaths per minute, rather than the normal 120. Its body temperature fell from 37 degrees Celsius (the same as a person) to just 15 degrees Celsius. Four hours after room air was reintroduced, the mouse was back to normal. 15

  The work in Roth’s laboratory had caught the attention of DARPA, which was looking for ways to ramp up medical capability on the new battlefields of central Asia. The Surviving Blood Loss Program was near the top of the wish list. Blood loss has been the leading cause of death in war, since at least the Civil War. Mostly thanks to improvements in response time and field hospitals, the proportion of troops who survive their wounds is higher, by far, in Iraq and Afghanistan than in any previous conflict the world has ever seen. 16 But blood loss still takes its toll. Not only is it responsible for the majority of deaths, but many of the survivors also face severe brain injuries due to lack of oxygen from blood loss.

  When it comes to helping soldiers, there are special constraints. Any tool has to be simple and small enough to carry in a medic’s pack. Jon Mogford, program director for the Surviving Blood Loss Program, says the military was looking for a silver bullet, something that could be administered in a single syringe. “Imagine that no help is on the way, fluids are gone and running low—we want to give [the medic] another tool to help save that soldier and buy time.” Buying time, that’s the goal. “Imagine being in the mountains of Afghanistan and compare that to a typical EMS pickup in the United States,” said Mogford.

  Even under the wing of the military, DARPA faces the same rules as academic or private research. Medics can’t start packing a new drug unless it has the same FDA approval as any other new medication. 17 That means starting in animal models. In Phase 1 of the Surviving Blood Loss Program, researchers would have to drain 60 percent of a rat’s blood in forty minutes and leave the rat for six hours before attempting resuscitation. With no medical intervention, the death rate is 100 percent. To pass Phase 1, a research team would have to bring the survival rate to 75 percent. The time frame: two years. The Roth lab did it. 18

  Since that early success Ikaria has taken important steps towards making hydrogen sulfide a usable medication. After mice there were experiments in dogs and pigs, which found that hydrogen sulfide reduced the damage from simulated heart attacks. 19 It’s done a bit differently in large animals—instead of a gas, they’re given a solution of sodium sulfide which breaks down to hydrogen sulfide almost immediately after entering the bloodstream. And the effect is not nearly so dramatic—this is not suspended animation. But the promise is still tremendous.

  Most exciting, while I struggle to wrap my mind around this, hydrogen sulfide has already been tested in human subjects. These early clinical trials, strictly to test safety and determine the proper dosage, found no significant harmful effects. 20 As Cheating Death is being written, the next round of human trials is just being launched—using hydrogen sulfide as an experimental treatment for heart attack and acute kidney injury. 21

  Dr. David Lefer at Emory University, who has worked with hydrogen sulfide and done work that’s similar to Roth’s, says he was surprised—and disappointed—to learn that it was so difficult to put animals larger than mice into suspended animation. 22 He speculates that swine—or people—may process the drug differently. He says suspended animation may someday be an option, but it will probably take a combination of drugs, and vastly more research. Still, he’s excited about the possibilities. In his own studies, mice given hydrogen sulfide suffered far less damage from simulated heart attacks. 23 Intriguingly, even if they were given a miniscule dose—so small it was undetectable within 15 seconds—the protective effect was still there, 24 hours later. 24 If the same effect were seen in humans, it could be a major help for transplant surgeons, who could give patients a dose of hydrogen sulfide a day before performing extensive, risky surgery.

  Whether the goal is suspended animation or a more mundane version, the principle is the same. When the body isn’t getting enough oxygen, you lower the need for oxygen—with poison gas, that’s the weird part. Hearing Roth explain this is more like watching a science fiction movie than reading a medical journal. “What you want to do is have the patient’s time slow down, while everyone around them moves at what we would call real time,” he said.

  Suspended animation has the ring of science fiction, but the basic concept is not so exotic. Think about hibernation. Bears famously spend the winter months more or less in slumber. But hibernation is common to a huge range of animal species, from frogs to turtles to certain birds like the bar-headed goose to mammals including squirrels, bears, and hedgehogs. In times when food is scarce and energy needs—keeping warm—are greater, these animals go into survival mode. Some of the adaptations go beyond simple hibernation; one type of squirrel, the Arctic ground squirrel, produces a chemical that allows its body temperature to drop below freezing without ill effects. 25

  Typically, hibernation is linked to two things: cold or body fat. Survival mode is triggered either when body temperature drops below a certain level or when the animal has packed on enough extra calories to last it through the winter. For this reason, hibernation times can vary. A bear will keep eating until it’s fat enough to survive the winter. During a winter that’s relatively warm, some ground squirrels won’t hibernate at all. Make it a cold one and they might snooze from November to March.

  In general, hibernation is a state where the need for energy is radically reduced. In ground squirrels, metabolism drops to
about 1 percent of normal levels. A squirrel running up trees (or through your attic) and gathering nuts for winter burns as much oxygen and calories in fifteen minutes as a hibernating squirrel burns all day and night. Not only is this fascinating science, but think about what it could mean for human survival. In a case of cardiac arrest, heart and brain tissue die because the lack of oxygen triggers a calamitous chemical chain reaction within our cells. If our body’s need for oxygen was 1/1000 of what it is, the process would unfold in super–slow motion. That damaging chain reaction might barely have time to get started by the time we reach a hospital and doctors shock us back to life.

  Until recently, it was thought that primates—monkeys, apes, and also humans—weren’t capable of such a dramatic transformation. But in 2004, animal physiologists in Marburg, Germany, revealed evidence of hibernation among dwarf lemurs living on the island of Madagascar off Africa. In the journal Nature, they wrote that these small primates spend several months a year dozing in tree holes, their body temperature drifting with the air temperature outside. 26 Now, here is something to consider: this state of hibernation isn’t triggered by freezing cold. In fact, Madagascar has a pretty inviting year-round climate; it rarely gets colder than about 50 degrees Fahrenheit.

  These languid lemurs may be smaller and furrier than we are, but in the family of nature, the lemur is a pretty close relative of human beings. The Marburg finding suggests the intriguing idea that other primates, including humans, might have instructions for hibernation somehow coded into our genes. In fact, it turns out we do have a lot in common not only with monkeys, but also other animals, including ground squirrels.

  Dr. Matt Andrews heads the Department of Biology at the University of Minnesota in Duluth, where he spends a lot of time thinking about ground squirrels. October is his favorite time of year, watching squirrels get fat for winter and dropping off to hibernate one by one. Andrews has a mischievous grin and an offbeat sense of humor. In our first five minutes on the phone, I learned that Goldy Gopher—mascot of the UMN sports teams—actually has the exact physical characteristics of a thirteen-lined ground squirrel and that Lawrence Welk bought his first accordion by saving up bounty money, a dollar at a time, from hunting ground squirrels and turning their skins in to state hunting officials. Ground squirrels used to be considered quite a pest in Minnesota—they still are by many people—but they’ve also become the focus of some heavy-duty research.