One of the first pieces of popular science writing was a two-part poem published in 1791 by Erasmus Darwin (grandfather of Charles Darwin) entitled The Botanic Garden. In his verses, he praises “vital air,” or the newly discovered element called “Oxygene”:
“… wed the enamour'd OXYGENE to LIGHT …
Whence in bright floods the VITAL AIR expands,
And with concentric spheres involves the lands…
Fills the fine lungs of all that breathe or bud,
Warms the new heart, and dyes the gushing blood…”
In this stanza, Darwin links oxygen to warmth and heat–an apt metaphor, since without either life ceases to function. However, we now know that life exists in a relatively narrow range of temperature and oxygen concentration; too little or too much of either is fatal to most organisms.
While hypoxia (low oxygen) or anoxia (no oxygen) lead to loss of cellular respiration, too much oxygen metabolized by the cell results in accumulation of reactive oxygen species such as hydrogen peroxide. These free radicals can damage cells directly or trigger an oxidative stress response, which protects the cell—to a point. Too much too quickly wreaks havoc in our organs and can lead to death.
Cold shock is its own stress response to extreme cold when genes activate to counter cellular damage done by freezing temperatures. Intriguingly, there are hints that cold can protect animals from oxygen-related stresses; for example, mild hypothermia is used as a therapeutic after cardiac events and for infants whose brains don’t get enough oxygen at birth.
“A decreased requirement for oxygen at lower temperatures has been known for over 150 years,” says Dr. Mark Roth, whose lab studies ways to protect tissues from oxygen deprivation and over-oxygenation (take a look at his work on the ways iodine can protect tissues during reoxygenation).
In a recent article published in Frontiers in Physiology, researchers from his lab looked at the interplay between cold shock and oxygen toxicity in the model organism C. elegans. This little worm is known to be sensitive to both cold shock at 2˚C and oxygen deprivation, with known genetic variants providing protection to either stress pathway.
The authors first looked at how oxygen deprivation and cold shock interact. They found that, while an atmosphere of pure nitrogen was toxic for the worms at room temperature, decreasing oxygen concentrations improved worm survival at 2˚C. At an oxygen pressure of 0 kilopascals (kPa), almost all of the worms survived for 48 hours in the cold. However, increasing this pressure up to 0.5 kPa lead to a sharp decline in survival (that’s still an incredibly low oxygen pressure: sea level is at about 20 kPa and the top of Mount Rainer at ~11 kPa). In other words, worms can survive 2 days in cold temperatures that would otherwise be lethal only when oxygen concentration is astonishingly low.
In contrast, they found that higher oxygen concentrations kills worms and prevents eggs from developing into adults within 8 hours at room temperature. This occurs specifically at hyperbaric pressures (>300 kPa), or with 100% oxygen infused into the habitat at high pressure. In the cold, hyperbaric oxygen becomes even more lethal, killing more than half of the worms within 2 hours. However, acclimatizing the worms to the cold by raising them at 12˚C before treating them with hyperbaric oxygen increases resistance to oxygen toxicity.
While cold adaptation increased oxygen tolerance, the authors next wanted to ask if cold adaptation is actually necessary for protection against oxygen toxicity. To answer this, the authors turned to known genetic mutants that are either sensitive or resistant to cold shock. Strains that cannot acclimatize to the cold had decreased survival in hyperbaric oxygen, while those that have enhanced resistance to cold shock also were more resistant to hyperbaric oxygen.
So, what is the mechanism? Antioxidants certainly play a role, as genetic strains that can’t make peroxidoxin or catalase proteins—which process hydrogen peroxide to be less toxic—also died more quickly in the cold. Pre-treating the worms with a diverse range of known antioxidants, including glucose, manganese chloride, or ascorbate, protected the worms from both cold shock and hyperbaric oxygen.
To summarize: too much oxygen is toxic for animals, especially at cold temperatures. The cold is also deadly, but taking away oxygen can dramatically increase survival. This finding “may help explain why people sometimes miraculously survive extreme cold when they are also deprived of oxygen,” says Dr. Roth.
Beyond the fascinating discovery that these two stress responses are related, Dr. Roth hopes that this work can have a clinical impact. He cites organ transplantation: donated organs are placed on ice during shipping, so would reducing oxygen in these packages preserve organs longer?
Erasmus Darwin believed that “the oxygene, or base of vital air, is the constituent principle of our power of sensibility.” He might be shocked to learn that oxygen is, in fact, a double-edged sword. Perhaps it’s time for an updated version to his poem.
This publication was also featured by the Fred Hutch News Service. Click here to check out their story.
Fred Hutch/University of Washington/Seattle Children’s Cancer Consortium member Dr. Mark Roth contributed to this research.
The spotlighted research was funded by the Army Research Office.
Suraci CM, Morrison ML, Roth MB. 2024. Oxygen is toxic in the cold in C. elegans. Front Physiol. Dec 24;15:1471249.
Hannah Lewis is a postdoctoral research fellow with Jim Boonyaratanakornkit’s group in the Vaccine and Infectious Disease Division (VIDD). She is developing screens to find rare B cells that produce protective antibodies against human herpesviruses. She obtained her PhD in molecular and cellular biology from the University of Washington.
For the Media