Cheating Death (9 page)

In the first chapters, I talked about death as a process, an ongoing chain of events that might be reversed with the right
intervention. It turns out death is generally caused not directly by lack of oxygen, but by a punishing cascade of chemical
reactions triggered by its absence and ultimately by its return. Lance Becker, the director of the Center for Resuscitation
Science, told me, “We used to think that once the heart is restarted, our work is done. Once you’re out of cardiac arrest,
it’s back to business as usual. But now we know that it kicks off a whole bunch of general mischief, both in the individual
cells of the body and in the system as a whole.”

The mischief creeps in as the minutes pass without oxygen. Cells switch to an ancient backup system: anaerobic metabolism.
Chemistry buffs know it as a form of fermentation. And then something dangerous begins to happen in the mitochondria, the
part of the cell that produces its energy. Becker’s colleague, Dr. Ben Abella, says, “You can make an analogy to nuclear power
plants. In a nuke plant, stopping production altogether is a dangerous process. So there are control rods that keep it firing
at a low, controlled burn. For some reason not well understood, when we stop blood flow and deprive the mitochondria of oxygen,
we start to lose the control rods.”

You might be surprised to learn that it gets even worse when oxygen is returned to the mix—for example, after a successful
resuscitation. “It’s a time bomb,” says Abella. “When oxygen comes rushing back, the control rods are missing. It goes nuts.”
The resulting damage, from the addition of oxygen to the mix, is known as reperfusion injury. The reintroduction of oxygen
leads to the production of a variety of toxic compounds, including free radicals and a variety of proteins, such as cytochrome
c, which triggers a type of preprogrammed cell death known as apoptosis.
⁸

Every cell in our body is coded with instructions for apoptosis. While it may seem counterintuitive, not to mention counterproductive,
under most circumstances cell death is a beneficial, even necessary process. As we constantly grow new cells, the old ones
have to go. When apoptosis malfunctions, the result is disastrous, uncontrolled growth: cancer.

Unfortunately, in the oxygen-generated chaos of reperfusion injury, apoptosis is a killer. This chain reaction—hard to stop
once it gets going—has caused much frustration over the years for doctors and paramedics. They could revive patients who had
been clinically dead for as long as an hour, but just getting back the heartbeat wasn’t enough. The vast majority of these
patients came back without meaningful brain function. They might as well have stayed dead.

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.”

*   *   *

W
HEN 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 reaction 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