To help people live, Mark Roth scrutinizes those who’ve come frighteningly close to dying.
People who have been lost in the frozen wilderness in a Mount Rainier whiteout or stowed away in the wheel well of a trans-Pacific jet. People who have suffered massive heart attacks or body-crushing car wrecks.
Roth sees a thread connecting these catastrophes with something seemingly quite different: immortality. Both conditions “press pause” on life, he said. It’s playing dead without being dead.
“There’s a connection that can be made easily between near-death experiences and immortality. Both of them aren’t doing anything — they’re in ‘suspended animation,'” Roth said. “And so there is something about a near-death experience, which is not so much near death, but what I call a far-death experience.”
It is admittedly trippy to equate being almost dead with living forever. But Roth, a biochemist and cell biologist at Seattle’s Fred Hutchinson Cancer Research Center, as well as an entrepreneur and past winner of a MacArthur “Genius Grant,” has built a career on making unlikely, unconventional, scientific connections.
His research could unlock significant medical advances, with clinical trials starting this year. The work has support from top national granting organizations and the U.S. Army, with an eye to aiding soldiers in combat. Colleagues praise his unique approach, one calling his work “seminal.”
As Roth explains his drive for medical research: “I want to make miracles happen more often.”
[Listen to Roth on GeekWire’s Health Tech Podcast, and continue reading for more.]
Many years ago, Roth became intrigued with reports of people who experienced suspended animation triggered by extreme conditions and were revived despite appearing to have been dead. The occurrence of frozen misadventures and stowaways, however, are too uncommon to support a research investigation. So he took a different tack. He started studying people who suffered severe stress: heart attacks; trauma; sepsis, which is a deadly condition caused by massive infections; and now COVID-19 cases.
“We study people who are having, if you will, experiences that bring them close to death, and then we try to understand what they’re doing and how that relates to whether they survive or not,” Roth said.
He was looking for the biological elixir that kept people tethered to life in the most dire situations.
A key ingredient for reanimation
Roth began with studies in animals in which he tried to mimic these states of animation. He found that he could de-animate and reanimate creatures from worms and zebrafish to mice by reducing their demand for oxygen. He did this by boosting their levels of sulfide and selenide, which are naturally occurring substances that we eat or breathe that are essential to life in low levels.
When you induce suspended animation in an injured person or animal, “you buy time for repair,” said Peter Radermacher, professor of Anesthesiology and Intensive Care Medicine at University Medical School in Ulm, Germany.
Radermacher recalled seeing in 2005 Roth’s research on mice and sulfide, which he used in the form of hydrogen sulfide. “It was a seminal paper,” he said. “It launched several thousand papers using hydrogen sulfide.”
That same year Roth launched a company called Ikaria to develop hydrogen sulfide-based treatments for people. The business was acquired for $2.3 billion by the U.K. pharmaceutical company Mallinckrodt Pharmaceuticals, but a few years later the biotech company stopped researching Roth’s de-animating, sulfur-based therapeutics.
Sulfide is deadly at higher levels, and some researchers questioned whether hydrogen sulfide treatment would work in larger mammals.
So Roth turned to bromide and iodide — close cousins to sulfide and selenide on the periodic table of elements. Bromide had already been used in medicine, beginning in the 1800s as a sedative, inducing de-animation. He wondered if in traumatic situations, our bodies could harness these elements in a different way than in normal conditions to help us survive.
“When you have a severe event, you either redistribute them properly — in which case you can get into your sleeping bag and survive that near death moment, in other words, de-animate properly and then you can be reanimated — or you don’t,” Roth said.
“So what are those redistribution events? Can you define them?” he asked. “And can you augment them to make it so that people who would have been dead are now not dead? That’s the goal.”
By analyzing blood collected from patients who experienced trauma or sepsis, he found a huge increase in iodide levels. But iodide’s presence in the blood didn’t reveal what it was doing — was it helping or hurting?
So Roth and his colleagues turned to animal models and discovered that boosting iodide levels in mice, pigs and rats led to better outcomes when they experienced traumatic events, compared to those that didn’t get the treatment.
The benefits come down to some basic chemistry. In the case of heart attacks, for example, blood flow is blocked and heart muscle becomes oxygen starved. It shuts down or de-animates. But when oxygen returns, there’s too much of it and hydrogen peroxide is produced. The hydrogen peroxide in turn wreaks havoc on healthy tissue, killing it. The iodide can act as a shield, chemically converting the hydrogen peroxide into oxygen and water and reducing inflammation. Damage averted. A reanimation success.
Dr. Sam Tisherman, professor of surgery with the University of Maryland’s School of Medicine, researches cooling a patient or “therapeutic hypothermia” as a way to treat trauma and cardiac patients. The cold temperature slows metabolism and gives surgeons time to operate.
“At some point you’ve got to give oxygen back, but how can you prevent that damage from the oxidative burst?” Tisherman said. Roth’s approach could help. “That would be complementary,” he said, “if it could work.”
The iodide connection
For Roth, it all added up. Not only was iodide a cellular superhero in humans, it was playing a stress response role in all sorts of organisms.
“The phenomenon of redistribution of these elements in moments of stress is not unique to people,” he said. “It is broadly present in biology.”
Take Arctic ground squirrels in Alaska. Researchers working with Roth were able to simulate in a lab setting the squirrels’ normal, winter hibernation. They sampled the blood from sleeping versus frolicking rodents. The iodide levels in the blood of the hibernating squirrels was two or three times higher than in normally active squirrels. Roth suspects that the elevated iodide helps the rodents safely recover from their state of suspended animation.
Another example comes from a brown algae, recognized in the Pacific Northwest as the massive bull kelp with its rubbery ribbons found near beaches. The nearshore plant contains some of the highest iodide concentrations of any organism. As tides ebb and flow, the kelp is exposed to sunlight and air that produce damaging hydrogen peroxide. Here again, iodide can limit the peroxide’s harm.
“What if the key to drastic survival stories,” Roth said, “comes down to what people were eating in the days and weeks before the trauma or accident?”
Roth’s overarching goal has been to apply his studies to healthcare. So in 2014 he launched Faraday Pharmaceuticals, a biotech spinoff from the Hutch. He is currently a board member and consultant for the Seattle-based company.
In October, Roth and a team of scientists published research showing naturally elevated iodide in hibernating squirrels, as well as in blood drawn from trauma and sepsis patients. The scientists also gave either iodide or saline injections to mice that experienced muscle damage to their hind legs, showing less damage to muscle tissue in the mice dosed with extra iodide.
The paper’s authors include scientists from the Hutch, Faraday, the Department of Emergency Medicine at the University of Washington, the Department of Surgery at Seattle’s Harborview Medical Center and the University of Alaska. The article was published in the journal Critical Care Explorations.
(One of the authors, Dr. Ron Maier, was also the surgeon-in-chief of the team that successfully treated a semi-frozen hiker who was recovered in November after being lost on Rainier.)
Most importantly, the research shows promise in the use of iodide in treating human patients as well. In 2019, Faraday scientists presented results from a study of 120 patients who experienced serious heart attacks. Patients who received an iodide-based drug created by Faraday had less damage to their hearts, according to the Phase 2 study results presented at an American Heart Association meeting.
This year, Roth and other researchers will start another Phase 2 study to look at the effects of providing intravenous iodide for trauma patients.
They will also embark on a more rigorous, Phase 3 study of heart attack patients and iodide treatment, which will take about two years to complete. If the outcomes are positive, the U.S. Food and Drug Administration would then evaluate the treatment for an additional six months, and it could become part of routine care.
Roth is hopeful that his insights into suspended animation will breathe life into the perilously ill.
The published study on squirrels, mice and humans “suggests that rapid increases of iodide in the blood could represent an ancient response to stress that is shared across animals,” Roth said. “If we can harness this capability, it could transform emergency medicine.”
