Cheating Death

by Sanjay Gupta

  Andrews, along with two UMN colleagues, is an adviser to a company called VitalMedix, which has gotten financial support from DARPA (the same military agency that funded the early suspended animation experiments of Mark Roth) and is currently working with the Army and Navy drug development offices. 27 VitalMedix is looking to develop a way to trigger hibernation in humans. Squirrels are the perfect research subject: they’re easy to find, you can keep them anywhere and they’ll eat anything. The Minnesota group feeds their squirrels pet food, Purina rat chow. They’re also easy to work with, at least compared to some research subjects. “We don’t do bears, because then you might have an experimental subject that would eat you,” says Andrews.

  The study of hibernation in a way completes a circle for Andrews. As a graduate student at Central Michigan University in the late 1970s, he got his start by studying how the heart could function at low body temperatures. As part of that research, he got interested in molecular biology, especially how genes effectively turn on and off.

  The genetic basis of hibernation was laid out in a 1998 paper, which identified genes that were triggered by a certain level of fat in the squirrel’s body. Since then, says Andrews, “We haven’t found a single gene in the ground squirrel sequence that isn’t in a person.”

  Having the genes isn’t the whole story, of course. Otherwise we’d all pack it in after Thanksgiving dinner and wake up around Easter. As we’ve seen in many fields of science and medicine, just as important as the genetic sequence are the triggers that “turn on” the relevant genes. The Minnesota team also knew that it would be unrealistic to instigate gene therapy on someone who just crashed their car or was bleeding out on the battlefield. They would need a shortcut. They would have to identify the molecular substances that actually carry out the body’s order to enter survival mode.

  “In 2002, DARPA contacted us about taking this approach to come up with ways to help the wounded soldier,” explains Andrews. “If a soldier suffers profound blood loss, we’d come up with a cocktail of ingredients that would essentially buy time for the injured soldier—more than just the minutes that CPR could buy or even the hours provided by hypothermia. DARPA was looking for more time than ever before, for the injured from an improvised explosive device (IED) explosion in Afghanistan to the car accident victim in Minnesota.” In essence, they were looking for near-instant hibernation.

  What VitalMedix came up with is a drug called Tamiasyn. It includes two vital components: an antioxidant to try and slow the damaging chain reaction that occurs when oxygen is removed from cells and an alternate energy source for these oxygen-deprived cells, so they won’t die. Finding the alternative fuel was an especially tough challenge, but Andrews found an interesting answer. He had noticed hibernating animals have high levels of ketone bodies, which are by-products that naturally occur when the body breaks down fatty acids during digestion. During hibernation, when digestion is unfolding in super–slow motion or not taking place at all, ketone bodies provide an additional source of fuel. 28 All of a sudden, suspended animation doesn’t sound like a science fiction novel. It is more like a biochemistry textbook.

  Another adviser to VitalMedix is Dr. Greg Beilman, a professor of surgery at the University of Minnesota and a colonel in the Army Reserves. He’s performed dozens of surgeries on battle-injured soldiers in Iraq and Kosovo. “My interest is personal,” he said. “I got interested in this after my deployment to Kosovo in 2000. There were a couple of things we worked on there: better ways to resuscitate people in the field and also how to better use resources in a field situation. I mean, when you’re in Afghanistan, six hours from a combat hospital, what’s the best way to stop the bleeding?”

  You can’t hike around an Afghan mountain range with a cooling box and a supply of chilled saline. You need something the medic can deploy when it’s pitch black and someone is shooting at his head—a drug that can be administered quickly and easily. In experiments on rats and pigs, Tamiasyn shows promise. The animals got the drug after going into shock from blood loss but before there was any attempt at resuscitation. In both kinds of animals, it lengthened survival time, and organ function actually improved as opposed to getting worse.

  Suspended animation and hibernation are two experimental approaches to saving trauma victims, but there are others, including the use of female hormones. It sounds pretty strange, but I was actually the coauthor on one of these studies, with colleagues at Grady Memorial Hospital in Atlanta. We found that giving the hormone progesterone led to better recoveries for people who suffer head injuries. Research on animals goes further; with the help of funding from DARPA, Dr. Irshad Chaudry at the University of Alabama at Birmingham has found that small doses of the female hormone progesterone can sharply improve survival from everything from sepsis to blood loss to cardiac arrest. 29

  Some doctors believe that progesterone evolved to function as a protection against blood loss in mammals, which often lose large amounts of blood during childbirth. 30 Jon Mogford of DARPA says the action of progesterone is actually more complicated than hydrogen sulfide. “Probably it’s a combination of anti-inflammatory mechanisms, preventing cell death and also controlling blood flow. We don’t know how it’s doing that in hemorrhagic shock, but it’s valid to presume that it would help survival.”

  Yet another approach involves—you might have guessed it—extreme hypothermia. A surgeon named Hasan Alam, at Massachusetts General Hospital, let us watch one of the surgeries. The test subjects are pigs. Alam knocks them out with an anesthetic, opens the chest, slices open the aorta—sometimes other major organs, too—and quickly drains about 60 percent of the pig’s blood. After a wait of thirty minutes, he inserts a catheter directly to the aorta and starts a pump that fills the animal’s heart and blood supply with a chilled solution of organ preservation fluid: a mixture of electrolytes and antioxidants that are typically used to extend the life of organs used in transplant operations. Forget moderation; Alam brings the temperature down to about 10 degrees Celsius (or 50 degrees Fahrenheit). It takes almost an hour to get the pigs that cold.

  At that point, he gets to the real work. “I can stop the [heart] pump. They have almost no blood in the body, no brain activity, no heartbeat, and it gives me plenty of time to fix the underlying injuries,” said Alam. Under normal circumstances, the internal injuries and massive blood loss would invariably be fatal to pigs, or to humans, for that matter, but in Alam’s lab, every single test pig has survived. A few days after surgery, he puts each pig through a few paces to assess their cognitive functioning. As best as he can tell, they suffer no brain damage at all. Even under the microscope, the brain cells show no sign of damage. 31

  If it works in people, this sort of procedure could have a huge impact in a hospital emergency room. Trauma is the leading cause of death for people under fifty and kills more under thirty-five than all other causes combined. 32 Alam said, “If somebody comes in tonight after getting shot in the chest, I’ll open the chest to control bleeding. If I can control it in just a few minutes, I think they’ll live. If it’s more like five minutes, they’ll probably die. But if I can get the brain temperature down like this, I’ll have more like two hours.”

  What all these approaches have in common is that they tinker with the cellular machinery that processes oxygen. Think back to what Lance Becker teaches: in a medical crisis like traumatic blood loss or cardiac arrest, it’s not just the loss of oxygen, but the body’s reaction that’s dangerous. Estrogen minimizes this reaction. Hypothermia puts it into slow motion. Hydrogen sulfide perhaps can stop the reaction altogether.

  If it all sounds far-fetched, especially the approach using hydrogen sulfide, remember that nature is full of creatures that can turn off the need to breathe. They’re everywhere. You can even find an example on the back of a comic book, next to the ads for X-ray specs and action figures. I’m talking about the mail-order ads for creatures called Sea-Monkeys. They’re actually a tiny kind of shrimp, marketed as “instant li
fe” or “real live fun pets you grow yourself.” Sea-Monkeys can survive without oxygen, in cysts, for as long as four years. Drop them into water, and as the sales pitch says, you get instant life for about three dollars, plus shipping and handling.

  It may be that creatures like this provide real clues to solving the puzzle of suspended animation. One person who believes this is Dr. Philip Bickler, an anesthesiologist at the University of California, San Francisco, Medical Center. In the operating room, he monitors patients during high-risk surgeries to repair brain aneurysms. An aneurysm is a blister on a blood vessel in the brain, caused by a weakening of the blood vessel wall. Sometimes, to fix it, a neurosurgeon has to first stop blood from flowing to the spot, usually by using a simple clip on the vessel.

  Since this cuts off blood flow to the affected part of the brain, the procedure carries the risk of brain damage. The same thing happens if the heart fails. “It’s usually said that if the heart stops beating, you’ll have severe neurological damage if it lasts more than five minutes,” says Bickler. “We try to buy more time.” To buy time, the anesthesiologist will try to reduce the brain’s need for oxygen with a mix of powerful drugs. Unfortunately, this safeguard doesn’t always work. During high-risk brain surgeries, a significant number of patients emerge with brain damage due to lack of oxygen. 33

  During a small number of extremely complex surgeries lasting an hour or more, some patients are put into deep hypothermia, much like Hasan Alam did in his swine experiments. For more routine aneurysm repairs, a number of doctors have tried the more modest version of hypothermia, cooling the brain to 33 degrees Celsius, but surprisingly—to Bickler, at least—a large clinical trial on this found no benefit.

  Like many doctors, Bickler had put a lot of faith in hypothermia. He decided to try and piece together what went wrong. When he thought about the experiment and why it failed, he reasoned that it must be because the bulk of the brain damage wasn’t taking place while the oxygen was cut off, which is when the patients were being cooled. The damage was coming afterward, caused by the body’s reaction to oxygen deprivation. Bickler figured that the same thing must be happening in people who suffered cardiac arrest.

  Bickler’s particular interest is blood chemistry, and his focus was on how that chemistry changes after the body is deprived of oxygen. We’ve seen that even a few minutes without oxygen will trigger a devastating cycle of inflammation and cell death, but it’s not exactly clear why that is so. Some lab rats, for example, can go without oxygen much longer than humans can before suffering brain damage. 34

  Many reptiles are even more resistant. Bickler’s current research looks at painted turtles, the kind you find in a pet store. Turtles breathe air, but in the wild during the winter, painted turtles will often burrow in the mud, without breathing for as long as four months. Low temperature is part of it, says Bickler, but not all. “Even when they’re warm, their tolerance of oxygen deprivation is about ten thousand times what it is in humans. The neurons in their brain are capable of entering a state of suspended animation when oxygen is not available. It’s essentially a reflex,” said Bickler. “If you force him [a turtle] to dive underwater, he’ll stay active for a number of hours, but then he’ll enter a state of quiescence, where he’s just minimally responsive. The metabolism is reduced to what I’d call a pilot-light level. It’s about one-tenth of 1 percent of normal.”

  The turtles stay in this state all winter, about four months. After just a few hours, Bickler has found, the animal has actually consumed every bit of oxygen in its tissues. It’s surviving on no oxygen at all. What we don’t know is just how it works. Bickler thinks the secret lies somewhere in the chemistry of calcium and potassium, which drive the basic energy production in each cell.

  Bickler has an unusual background for a physician; he started off as a marine biologist. At the world-famous Scripps Institution of Oceanography in San Diego, he marveled at the adaptations various animals made to survive. When we first spoke, he told me about a creature called the Antarctic ice fish. It lives along the sandy sea bottom, underneath the ice shelves of Antarctica, in temperatures which dip below 30 degrees Fahrenheit (the ocean’s salt content keeps it from freezing at 32 degrees Fahrenheit). To manage this trick, the fish actually produces a type of antifreeze in its blood, which prevents ice crystals from forming. It also manages to circulate oxygen without using red blood cells; this makes the blood more fluid and conserves energy in the extremely harsh conditions. Asked if we might artificially produce the same effect in people, Bickler points to isoflurane, a common anesthesia drug. It’s used in surgeries where the patient is cooled, because it seems to protect cells at low temperatures—by affecting the balance of potassium, if you are wondering.

  Bickler says, “I’ve been an anesthesiologist for twenty years, but my heart is still with those turtles and fish and hibernating creatures.” They’re still a part of his professional life; in 2008, he won a grant for a study of diving marine mammals—whales and dolphins—to examine how their neurons can adapt to low oxygen levels. Some marine mammals will stay underwater for more than an hour while hunting for food.

  Bickler switched to the study of medicine to see if he could find a practical application for some of this biology. If animals could survive harsh conditions by lowering their body temperature or slowing their metabolism, perhaps there was a way for humans to trigger the same survival mechanisms in their own bodies. Bickler is an avid mountain climber, and had already seen the human body is more adaptable than many people know. In air as thin as it is on top of Mount Everest, an unacclimated climber would be dead in an hour. But it’s a different story for expert climbers who train for months before an ascent and work their way up the mountain by staying for a few days at each successive altitude. These mountaineers manage not only to survive, but to survive without the help of supplemental oxygen, even while climbing to the summit of Mount Everest. 35 What Bickler eventually hopes to find is a way to speed up those adaptations in a way that might be utilized as part of emergency medical care. Perhaps we can develop a drug that’s akin to the chemicals naturally found in a turtle, which would give us some of that same amazing survival ability.

  In his lab in Philadelphia, Lance Becker is thinking something similar. He says that all the death pathways, all the mischief, all the chemical chaos, seems to take place in the mitochondria—the part of the cell that produces energy. Some evolutionary biologists say death, the way we know it, didn’t even exist until cells became complex enough to include mitochondria. These scientists say the mitochondria in our cells actually evolved from primitive bacteria. Bacteria do not have mitochondria and do not undergo apoptosis. They simply divide, again and again, as long as conditions are favorable. Bacteria might be eaten or destroyed, but otherwise, they just hang around, becoming spores or entering some other form of quiescence.

  Becker’s focus is on clinical practice—how to stop or reverse the death pathways when the body is deprived of oxygen due to cardiac arrest, trauma, or some other cause. Hypothermia is one tool, so is CPR. The next step, he says, could be drugs like the ones being tested in Mark Roth’s laboratory. Hydrogen sulfide does work on the mitochondria, binding itself to the electrons within that organism. Says Becker, “A number of us are pursuing this very similar science.”

  When we spoke, Roth contrasted his approach to what EMTs typically do when they arrive to help a cardiac arrest victim. “The very first thing they do is to slap a mask on their face and give them 100 percent oxygen. But perhaps another idea could be tried,” he says. “That is to take away the little bit of rope they’re using to hang themselves, to prevent them from using the little bit of oxygen that’s killing them.”

  When Roth looks around this world, he sees hints of immortality everywhere: in hibernating squirrels, in skiers who survive a plunge through the ice, in the spores of bacteria, in the seeds of plants and in our own bodies. He sees immortality as inextricably linked with quiescence. Quiescence, as he describe
s it, is a state of unchanging readiness. Again he says, “Look at female germ cells [eggs] in an ovary, all sitting there like a fireman waiting to fight fires. Only one a month, of a bazillion, goes out. The others sit in the fire station, doing nothing, for decades at a time.”

  In smaller and simpler organisms, we find examples so stark that they fall in a different category. Some bacteria spores—including dangerous ones, like anthrax—can last for years without any outside nourishment in a complete unchanging state. Many viruses do the same. Eggs, seeds, spores, viruses—what these hold is the potential for life. Says Roth, “All these things with proliferation potential seem to have this remarkable quality, which is that they can sit in suspended animation for this remarkable period of time.”

  One thing to keep in mind—as a treatment for humans or other mammals, hydrogen sulfide as used by Ikaria does not induce suspended animation, the way it does in roundworms. It’s still the dimmer switch. For now, Roth says he just wants to develop a drug that can be used in a conventional medical setting, alongside other therapies like hypothermia. But I couldn’t help but wonder: is it really impossible to think that we might someday stop time—put humans into suspended animation, the way Roth did with his baby zebrafish?

  “Of course that [research] is far more in its infancy,” says Roth. “For now I think it’s more straightforward to enable the physician to utilize this technology by simply dimming the patient, rather than starting from an extreme situation where they lose a lot of control that they have.” But with a mischievous grin, Roth admits he doesn’t really know how far this could go.