Cold air makes oxygen toxic for worms

Most people who try to hitch a free flight hiding in a jet’s wheel-well die in the attempt, like the person whose body was discovered on Christmas Eve after a flight from Chicago landed on Maui. 

But occasionally someone survives the extreme cold and oxygen deprivation of flying several hours at a high altitude outside the plane’s pressurized and warmed passenger cabin.

When skeptical reporters ask doctors how survival is even possible under such extreme conditions, they’re told that in rare situations, a combination of hypothermia and anoxia could trigger a state of suspended animation that keeps the stowaway alive long enough to survive the journey.

Such stories have long fascinated Mark Roth, PhD, a biochemist and cell biologist in the Basic Sciences Division of Fred Hutch Cancer Center.

A new study from a postbaccalaureate researcher in Roth’s lab, Cameron Suraci, shows that microscopic worms exposed to frigid temperatures (about 36 degrees Fahrenheit) can survive up to 48 hours if they’re also exposed to low oxygen.

The study, published late last month  in the journal Frontiers in Physiology, identifies physiological responses that overlap in microscopic worms when they are exposed to extreme cold and low oxygen simultaneously. Some of the findings included: 

• The oxygen that keeps worms alive at room temperature becomes toxic in frigid conditions, killing the worms before the cold gets them.
• Worms acclimatized to moderately low temperatures show resistance to high levels of oxygen at room temperature.
• Worms exposed to greater than normal concentrations of oxygen are more sensitive to the cold than worms exposed to normal oxygen levels.

Hypothermia shields the worms against the effects of anoxia, and anoxia blunts the stress of hypothermia, resulting in a higher survival rate for both lethal conditions than for either one alone.

The evolved synergy of those stress responses suggests that a similar phenomenon may be at work in humans who survive both extreme cold and oxygen deprivation.

Learning the ways of worms

The discovery is an early career success for Suraci, the study’s lead author, who earned his Bachelor of Science degree in biochemistry from the University of Washington in 2023 but ran into a brick wall of graduate school rejections.

PhD programs have become increasingly competitive, favoring applicants who already have extensive lab experience and even authorship on published scientific studies as undergraduates.

Suraci’s hunt for a research technician position led him to the Roth Lab a few weeks after graduation.

Roth has long explored how humans and other animals navigate the mercurial boundaries between life and death, whether it’s by appearing dead during hibernation or surviving a flight in the wheel well of jet.

Roth and staff scientist Mike Morrison, PhD, both co-authors on the study, liked the potential they saw in Suraci and wanted him to get going quickly on understanding oxygen toxicity in the microscopic worm Caenorhabditis elegans.

Morrison advised him to put in some hours just watching C. elegans wriggle around under a microscope so he would know how they act normally before exposing them to different temperatures and oxygen concentrations.

The worms undulate with a hypnotizing S pattern that propels them like a snake across sand. It’s hypnotizing and hard to forget.

“I had never done anything with worms,” Suraci said. “One of the first things I did here was I spent a very long time just observing their behavior and then when I went to bed that night, I closed my eyes and they were just like crawling across my field of vision. My whole brain had been dedicated to figuring out how these things work.”

Reponses to two lethal conditions synergize to improve survival

Life needs oxygen and heat within a certain range for survival. Too much or too little of either is fatal.

Suraci confirmed in one series of tests that exposure to pressurized room temperature air that is too rich in oxygen kills worms. He also confirmed that low temperatures make that oxygen-rich air even more toxic.

However, he discovered that worms that had been previously acclimatized to cold temperatures showed some resistance to room-temperature hyperbaric oxygen (high concentrations of oxygen under pressure).

He speculated that manipulating genes involved in a molecular pathway that helps the worms acclimatize to lower temperatures would achieve the same effect and found an overlap between pathways that enhance cold tolerance and the pathways that enhance tolerance to oxygen.

“It was pretty surprising how well these pieces matched up, especially the fact that we were able to create sensitivity by getting rid of genes necessary to activate this stuff,” Suraci said. “How would hyperbaric oxygen activate the cold acclimatization pathway?”

The finding suggested that oxygen becomes more toxic the colder it gets, and worms have evolved some mechanisms acclimatizing to colder temperatures that also fend off that toxicity.

“No one has really talked about oxygen toxicity being what kills you in the cold,” Suraci said. “The fact that cold acclimatization is giving you protection against oxygen suggests that a big, big part of it is that oxygen is becoming more toxic as you get colder.”

More research is needed to understand the relationship between oxygen and temperature in humans and other animals.

Doctors already use cooling to prevent brain damage in oxygen-deprived infants, but whether low oxygen also confers protection against the cold — or whether high oxygen is more toxic to humans in low temperatures — is less understood.

Suraci hopes the publication will strengthen his application for graduate school this year.

This research was supported by grants from the Army Research Office.