A video of one of the nine-hour-long experiments, sped up 30-fold, initially shows a brown mouse darting manically about its quarters, sniffing and munching its rations. Next comes the dose of hydrogen sulfide. The animal collapses, lying motionless in the straw without so much as a shudder or twitch. Finally, the air is turned back on, and—voilà—the mouse is back to sniffing and munching. Remarkably, while in the resting phase, the mouse’s core temperature drops to match that of the environment, a cool 57ºF in this case. “I’m cooling the body in order to slow down metabolic rate,” Alam says. “Roth is slowing metabolic rate, and the temperature comes down as a by-product.”
In the future, ambulances and trauma wards could routinely include equipment needed to maintain life in a state of suspension until surgeons can repair the damage.
Like oxygen deprivation, hydrogen sulfide retards metabolic activity by tweaking the body’s main power-generating apparatus. Oxidative phosphorylation is mediated by an enzyme called cytochrome c oxidase, which binds to oxygen and shuffles its electrons around to produce molecules of ATP. But hydrogen sulfide, which is chemically similar to oxygen, attaches itself to cytochrome c oxidase with even greater affinity. In fact, the body naturally produces trace quantities of hydrogen sulfide to help regulate metabolism. At higher concentrations—just beneath the toxic threshold—the gas educes a latent hibernation response that appears to reside in all mammals, including humans.
With this in mind, Roth figured he could keep animals alive in a severely oxygen-sparse environment by simply reducing their respiratory demand. Following this logic, he put mice in a vessel of 5 percent oxygen, a level at which the animals die in less than 15 minutes. But before locking the mice in the chamber, Roth gave them a 20-minute hit of hydrogen sulfide, to rein in their metabolism and reduce oxygen needs. The results were astounding: All the mice survived in experiments that ran for hours. “We have done this for six hours, and we don’t lose any of them,” he says. “We just stop the experiment because we get bored.” As in the previous study, the rodents are no worse for wear.
Based on this track record, Roth has cofounded Ikaria, a company that will try to apply these techniques to humans. Ikaria has already shown that sulfide-induced hibernation works in pigs and dogs, animals physiologically similar to humans, and has a marked clinical benefit when used to treat injuries in these animals. “We’re developing a variety of formulations and testing them in appropriate large-animal models of human disease with an eye on taking one or two of them into the clinic in the near term,” says Steve Gillis, the company’s CEO.
It is difficult to overstate the impact these techniques could have on health care, particularly in the treatment of patients with severe injuries. Be they from car crashes, falls, exposure, or work-related incidents, accidents are the fifth-leading cause of death in America and the number one killer of people under age 44, resulting in more than 49,000 deaths a year. The Centers for Disease Control estimates that the 50 million new injuries seen annually cost up to $406 billion to treat. In the vast majority of cases, terminally wounded patients die either on their way to the emergency room or soon after getting to the hospital because they bleed to death before receiving proper surgical care.
In the future, ambulances and trauma wards could routinely include equipment needed to maintain life in a state of suspension until surgeons can repair the damage. “If you get in a car accident today, what are they going to do? Call 911 and put you in an ambulance with a breathing tube and an IV and drive as fast as they can,” Alam says. “Once you get to the hospital, there are not many things we can’t fix anymore. The problem is that by the time most people get to the hospital, it’s too late.” Cooling equipment and portable sulfide gas masks could greatly improve survival rates among critically wounded patients by forestalling blood loss, cellular breakdown, and the buildup of toxins—ravages that trigger permanent disability and death. “If we can slow down life processes so that you don’t require oxygen and the entire body is preserved for a few hours, that buys us precious time to fix the injuries,” Roth says.
These methods would nonetheless entail a radical departure from conventional medical practice. Roth argues for a new philosophy to accompany a new standard of care. “Really, there is alive and there is dead, and then there is a third space which is neither alive nor dead,” he says. “We can call it potentially alive but at the moment not alive.” As medicine steadily encroaches on the dreams of science fiction, visits to this liminal space may one day seem no more unusual than a trip to the emergency room.
