The ultimate comeback: the science of resurrection

I thank You God for most this amazing day: for the leaping greenly spirits of trees and a blue true dream of sky; and for everything

which is natural which is infinite which is yes

American poet e.e. cummings wrote this, apparently on Easter Sunday. He continues: "(I who have died am alive again today, and this is the sun’s birthday; this is the birthday of life and of love and wings."

Associating rebirth with cycles in nature isn't just a Christian or even religious thing. In temperate climates, especially, every year life that seems to die in autumn is resurrected in spring. Even where trees don't drop their leaves and the earth doesn't sleep under a blanket of snow, subtle changes may indicate a slowing, a retreat, a sense of suspended animation. And now, in the spring, as sap begins to flow, buds begins to form and shoots begin to sprout, life is resurrected. Animals emerge from hibernation, like Sleeping Beauty woken from her death-like 100-year sleep.

But some animals, and a few other organisms, take the analogy one step further: apparently dead, they then, it seems, come back to life.

Take the weirdly cuddly-looking tardigrade — like a cross between a tank and a teddy bear, and renowned for its indestructibility. Under extreme conditions, tardigrades may engage in cryptobiosis, a process in which they may become completely dehydrated and roll up into a little ball called a "tun."

"Tardigrades form tuns by contracting their musculature and simultaneously expel water, which results in a decrease in overall volume," Derrick Kolling, chair of the department of chemistry at Marshall University and head of its tardigrade-focused Kolling Lab, told Salon.

The tardigrade is then said to be in the "tun state." It can stay like this for weeks before reviving under more favorable conditions. Some species have been shown to resurrect quite well (that is, a substantial proportion of studied individuals survived) when rehydrated after more than seven months of cryptobiosis. And after two weeks of exposure to the vacuum of low orbit space while in their dried-out state, tardigrades came "unambiguously" back to life (although after two years of that treatment, which also involves exposure to cosmic radiation, there was no resurrection). In another study, one species of tardigrade revived after 20 years as a dried-out little ball.

"One criterion for something to be considered living is metabolic activity," noted Kolling, "and even in the extreme case of a complete pause in metabolism, tardigrades still possess a network of enzymes that can catabolize and anabolize — in this situation, I would consider them alive. Would you consider a cryopreserved human ‘dead’?"

... Or don't. Naked mole rats are unique mammals in many respects. They have complex social lives, for example. They're eusocial, a description applied to animals — including bees, wasps, a few other insects, some snapping shrimp and these odd mammals — that have complex social organization involving overlap of generations, cooperative rearing of young, and non-reproducing worker castes. Their blood temperature fluctuates with the ambient temperature, a rare trait among mammals that they share with the sloth.

Perhaps most amazingly, they are able to — apparently — die for a little while when ambient oxygen levels are extremely low, or completely absent. That's right: In the tunnels in which naked mole rats spend their lives, humidity levels can approach 100% and carbon dioxide accumulates thanks to dozens of the wrinkly little guys exhaling in the already very low-oxygen environment. So naked mole rats are chronically oxygen-deprived, but in the lab researchers have confirmed that they can survive for a little while with no oxygen at all.

"In nature, naked mole rats are not exposed to anoxic (0% oxygen) [conditions], but when they were exposed to it in the lab, they did survive for 18 mins which in itself is very impressive! In their tunnels, it is debated whether they naturally experience hypoxic (low oxygen) conditions, but when they are exposed to these conditions in the lab, they do undergo metabolic rate depression," Hanane Hadj-Moussa said to Salon. Currently a research scientist at the Brabraham Institute in Cambridge, UK, where she studies the metabolic adaptations and advantages of ageing, Hadj-Moussa did her doctoral work at the extreme adaptation-focused Storey Lab at Carleton University in Ottawa, Canada, where she studied the metabolic adaptations animals make to cope with extreme environments.

Reducing the metabolic rate and slowing the heart is an adaptation naked mole rats share with most resurrecting animals. But they also have a unique adaptation: switching their energy source from glucose to fructose.

"This is an odd adaptation but allows them to perform anaerobic glycolysis," Hadj-Moussa explained. This means that during those low oxygen periods, they're able to generate energy from fructose without needing to use scarce oxygen to do so, as generating energy the usual way, from glucose, would require. "They activate neuroprotective and cardio protective mechanisms to limit damages."

Then, when it's time for resurrection, Hadj-Moussa explained, "they 're-animate' by reversing what they did to depress their metabolism, shift back to glucose metabolism, all while elevating levels of antioxidants."

As with the world that freezes in winter then thaws back to life, resurrection often involves the cold. Among these is the wood frog, a Canadian amphibian that freezes solid for eight months of the year.

"One of the main protective adaptations the frogs have is their ability to simultaneously dehydrate their cells while pumping them full of glucose to prevent and minimize ice crystal formation inside cells, which is much more dangerous than freezing their body water in their extracellular spaces," Hadj-Moussa, who studied wood frog freeze tolerance during her time in Ottawa, told Salon. Each molecule of glucose, she explained, surrounds itself with water molecules. The glucose prevents the water from forming cell-slashing ice crystals, lowering the temperature required for it to freeze. And since the cells have also been dehydrated, there is less water inside them. About 70% of the body water that gets frozen in the wood frogs is frozen outside their cells, in those "safe" extracellular spaces: inside the abdomen and in sheets between their skin and muscles.

The first ice crystal that forms on the wood frog's skin triggers a cascade of chemical signals that "prepares the frog to undergo freeze tolerance and metabolic rate depression. This cascade leads the liver to produce massive amounts of glucose, [adjusts] the heart rate to make sure the heart can pump the glucose-rich blood to all the cells that need it, and this starts to slow organs down and turn on protective mechanisms," Hadj-Moussa said.

Some years after also working on the wood frog in Ottawa, another Storey lab alumna, Rasha Al-Attar, now works at Harvard Medical School and the Massachusetts General Hospital Center for Engineering in Medicine & Surgery, where she takes inspiration from nature to develop cryopreservation techniques for experimental model animals like zebrafish, or to preserve organs like human hearts.

The mechanisms animals use to hibernate or slow their metabolism during unfavorable seasonal conditions are similar to those used by resurrecting creatures, who are just rather more extreme about it. As Al-Attar and her M.Sc. supervisor, Ken Storey, wrote in a 2020 paper, "while there are many forms of metabolic rate depression, the underlying theory remains the same ...energy expensive non-critical and or harmful cellular and metabolic processes ... are greatly reduced and the finite amount of energy reserves available are allocated to promoting pro-survival processes" such as the wood frog's self-cryopreservation.

Enduring extreme conditions is one thing. Then there's thriving in them. When you can do that, you're called an extremophile. Extremophiles form another group of resurrectors. Many are bacteria or other microbes. Luis Andrés Yarzábal, a microbiologist at the Universidad Católica de Cuenca in Ecuador, described the surprising findings of Russian scientists studying ice cores extracted from pristine glaciers in Antarctica in the 1980s.

"When they started to look at them with a microscope, they discovered plenty of microbes. Many were dead, of course, but others were alive and reactivated very, very rapidly. Now we call this process of reactivation "resurrection," and this word is used on purpose because, in fact, they can be in a kind of sustained life state for millions of years. In fact, bacteria can remain frozen and alive for at least 3.5 million years, and they recover very rapidly, they reactivate," Yarzábal told Salon. "In fact, this is what we [as scientists] do to preserve our bacterial strains, we freeze them, in our ultra freezers at minus 80 degrees. So this is no surprise that microorganisms can remain not only alive, but viable, which means that they can start dividing again."

Organisms that can survive in this suspended, or anabiotic, state, Yarzábal explained, include not just extremophile bacteria but also viruses, fungi, protozoa and microscopic animals called nematodes. Salts dissolved in the water ensure a very tiny amount of water remains in a liquid state in the interface between ice crystals. Microorganisms can be displaced to this tiny space, where they avoid being injured by the crystals of ice and remain alive although their metabolic rate stays almost imperceptibly low, so they are expending practically no energy on life functions, instead biding their time until conditions improve.

For e.e. cummings, like earlier American transcendentalist poets like Ralph Waldo Emerson and Henry David Thoreau, paying attention was everything. And when nature's creations perform acts magical enough to be described as resurrection, there's so much wonder to attend to. This time of year invites us all, believers and atheists alike, to emerge from our own suspended animation or curled-up little balls, like cummings writes at the end of that poem:

now the ears of my ears awake and now the eyes of my eyes are opened