Inducing hypothermia in a human is a brute-force attack. The biological thermostat is hardwired, so to cool someone beyond their safe zone it’s necessary to overwhelm the body’s ability to stay warm. “The body tries everything it can to keep the temperature up,” says Cheng Chi Lee, professor of biochemistry and molecular biology at the University of Texas. “Until you reach a point where it no longer can, and then the body will cool.” However, the goal of clinically induced hypothermia is to suppress metabolic activity, protecting tissues when they become starved of oxygen. Hypothermia is a powerful and reliable way to achieve that, but Lee has stumbled upon another way.
As a young biochemist, Lee became intrigued by a gene called Clps. Normally it is only active in the pancreas, but when mice are kept in constant darkness the gene switches on in all tissues. “At that time, when I discovered this really fascinating phenomenon, I was wondering, why would nature design such a thing?” says Lee. “Why would nature turn on a gene when you keep an animal in constantly dark environments? And it occurred to me the most likely time you’ll find animals in a state of constant darkness is when it goes into hibernation or a long period of torpor.” The gene codes for colipase, an enzyme that breaks down fat, and its affinity for darkness suggests that it is designed to switch on when animals are ensconced in their burrows for extended periods.
Although animals can be induced to enter low metabolic states with the right combination of temperature, darkness, and restricted food supply, how these environmental cues are communicated to the individual tissues is still not fully understood.
Although animals can be induced to enter low metabolic states with the right combination of temperature, darkness, and restricted food supply, how these environmental cues are communicated to the individual tissues is still not fully understood. Lee realized he could use Clps activation to report the end of that chain. But the middle was still missing. His team administered various proteins to see if they could activate Clps in mice kept in normal day-and-night conditions, which would not normally prompt torpor. After seven years, their search had turned to a molecule called 5-prime-adenosine-monophosphate (5’AMP), found naturally in mice as part of a system to regulate cells’ energy supply.
As usual, one of the researchers injected a mouse with the candidate molecule and prepared to take a sample to look for Clps activation. But when he picked it up, he was shocked to discover the animal was cold. Unlike true hibernators, mice never let their temperature fall very far during torpor periods. “I was shocked that the body temperature would drop to 1 or 2°C above ambient temperature,” says Lee. “And yet the mouse was completely viable after its body temperature returned to normal.” The team had accidentally discovered a molecule that could very rapidly induce profound hypothermia in mice without aggressive cooling. Mice treated with 5’AMP rapidly fall into coma-like states, in which their breathing and heartbeat are slowed. Meanwhile, their temperature drops to just a few degrees higher than the surrounding environment, far below the point that would normally kill them. And yet, left alone, the mice recover spontaneously without showing any negative effects.
This time, it wasn’t hypothermia driving the drop in metabolism. The mice were entering low metabolic states, and their temperatures were dropping as a consequence. As their metabolism slowed, the mice were unable to make up the heat lost to the environment, and so they became cold. Somehow 5’AMP was shutting down the mice’s metabolism and putting them into a state of suspended animation.
Lee is now trying to discover what sets the time limit for 5’AMP-induced torpor. Although 5’AMP induces a state of suspended animation, it is markedly different from true torpor. For some reason, mice given artificial doses of 5’AMP do not burn fat, instead rapidly using the available glycogen in the body. Lee speculates that this energy demand might be the reason the mice rouse themselves again. No one knows for sure, but Lee is hopeful he can unravel the secrets of the mysterious suspended animation drug. “A lot of the time it’s luck, a lot of time it’s observation,” he says about his research. “And a lot of the time it’s nature being kind to me when I ask the right questions.”