Cheating Death (10 page)

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.

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.”