Philip A. Kramer
Since the beginning of recorded history, humanity has fought against the ravages of time. Often time passes at a snail’s pace and separates us from where and when we want to be. At other moments, it is gone before we can appreciate it, leaving us longing for the irrecoverable past. Eventually, time runs out, and even the luckiest of us succumb to age. But it is not in human nature to give up without a fight, even if it means standing our ground against time itself.
Ancient cultures preserved their dead, embalming the bodies with herbs, spices, salts, vegetative matter, or clays, and drying the bodies before burial. Many believed that, in doing so, the fragments of the soul would remain together, giving them life after death, and perhaps a body to reclaim one day. Embalming practices continue to this day, but with chemical fixatives. But perhaps the most impressive instances of human preservation were those that occurred unintentionally, such as the Tollund man, the La Doncella Inca Maiden, and Ötzi the Iceman, who were found centuries to millennia after their deaths . While the appearance of life is convincing, it is a poor facsimile. But for some divine intervention, these bodies will not return from death.
Suspended animation achieved by scientific means, on the other hand, just might work.
Suspended animation is a growing area of research that seeks to make death itself reversible, to restore activity to a silent brain, and make a stopped heart beat again. With this technology, organs can be preserved for transplant, lethal injuries can be repaired while a patient lays frozen in time, and our genetic legacy can be carried into the future.
Stasis in Fiction
Image courtesy Jody Lynn Nye. Visit website here.
Suspended animation is otherwise known as stasis, but stasis has a wider definition in science fiction. Some think of the temporal field projected by a starship to freeze an enemy ship in space. That degree of temporal manipulation is far beyond us, and one I am not qualified to talk about. Instead, I will discuss the biologist’s version of stasis; the technique used to slow or even stop all signs of life, and eventually start it up again. This has been a tool used for decades by science fiction writers. With it, some of our favorite characters have reached distant worlds, visited the future, or been saved from deadly injuries.
The most common methods of suspended animation today are desiccation and cryopreservation. Desiccation is attractive to science fiction writers for its dramatic visuals: a body shriveling until it is nothing more than a fragile husk to be rehydrated later. Liu Cixin, the author of The Three Body Problem, uses this desiccation method for a race of aliens based out of Alpha Centauri, who must endure a long transit to Earth. Cryopreservation, however, is the most popular form of stasis in fiction, whereby individuals enter a specialized pod which preserves them in a cryogenic slumber. Stasis pods have been used in fiction to preserve the injured on battlefields or by cryogenics companies that promise to transport the deceased or terminally ill to a future where they can be revived or cured or their consciousness digitized (e.g. Dennis E. Taylor in We are Legion and Lois McMaster Bujold in Cryoburn). I have seen humanity outlive global catastrophes by preserving their genetic legacy on an orbiting space station (e.g. Neal Stephenson in Seveneves) or by waiting out the apocalypse in stasis in an underground facility (e.g. Hugh Howey’s Shift Omnibus). Stasis has been used for dramatic effect by suspending characters for decades only to have them wake to a vastly different reality (e.g. Anne McCaffrey and Jody Lynn Nye in The Death of Sleep and Darren Wearmouth and Carl Sinclair in Sixth Cycle). But science fiction writers did not dream up suspended animation on their own. It already exists in nature.
Suspended Animation in Nature
Many organisms have evolved a suspended animation technique of their own. From the smallest of bacteria to large, multicellular amphibians and mammals, stasis helps sustain life through drought, and freezing temperatures. Cryptobiosis is the term used to describe this biological adaptation, and it is characterized by a dramatic decrease in the metabolic rate of the organism .
Many small organisms can survive for years in a desiccated state. These organisms have evolved to survive harsh climates or wait out food and water shortages. The simplest of organisms, bacteria and fungi, can produce spores capable of being revived after millions of years, while some plant seeds can be sprouted after a thousand years of dormancy [3,4]. These organisms purposely dehydrate, removing as much water as possible from their cells. Without water, there can be no life.
Perhaps the best example of this is the tardigrades, water bears, which can lose nearly all of their water, survive the vacuum of space, radiation, and extreme cold, and live again once rehydrated [5,6]. Some complex organisms can achieve a similar state of suspended animation. You can order the dry eggs of some crustaceans, Triops and brine shrimp, and hatch them in water months later. The African killifish, a vertebrate used frequently in aging research, has a short lifecycle due to the frequency of drought. It can lay eggs in the bottom of dry pools. The African killfish then hatch after the rains return months later.
Hypsibius dujardini, image by Willow Gabriel; Triops image by Steve Jurvetson; Killifish image by Andreas Wretström, all courtesy Wikicommons.
Rather than remove water entirely to achieve suspended animation, it can be frozen. All it takes is cold temperatures, and a site of nucleation, and a lattice of water molecules will form, encasing cells in a tomb of crystalline ice.
Microorganisms and small, multicellular organisms can live indefinitely while frozen, often without any evolutionary adaptations. This has some people worried. If global temperatures rise, the permafrost will melt, potentially releasing many ancient and deadly bacteria and viruses. Plagues thought long burned out could be lying in wait beneath the ice.
Larger organisms are another matter. Because of the complexity of their organ systems and the fragile nature of many of their cells, multicellular organisms have had to evolve a defense against the cold to avoid freezing completely. Many frogs, for example, have evolved to survive entire winters frozen almost solid (two-thirds ice) . Heart and brain activity stop, and do not start again until the first spring thaw [8,9]. Nucleating proteins in their blood allow small ice crystals to form outside their cells, preventing cell damage. The formation of this ice also draws water from cells, but the frog combats this by producing large quantities of glucose. When taken up by cells, the glucose prevents them from dehydrating during the freezing process. Some other species, like some fish, plants, and insects, have antifreeze proteins, or other protective molecules that interfere with the formation of crystalline ice .
They aren’t the only creatures who’ve shown remarkable adaptation to the cold. The arctic fruit fly, Chymomyza costata, can survive being dropped into liquid nitrogen (-321˚F). Interestingly, Drosophila melanogaster, the average fruit fly can survive freezing with supplementation of a particular amino acid present in their arctic cousins .
Arctic Ground squirrel image by DJ Kast, courtesy Wikicommons; Wood frog image by Brian Gratwicke, courtesy Wikicommons. Dwarf lemur image by David Haring, courtesy Duke Lemur Center.
Other arctic species, such as the arctic ground squirrel, can also survive sub-freezing temperatures. No ice forms within the body of the squirrel, yet its core body temperature can fall below freezing during its winter hibernation. It achieves this by using a super cooling technique, giving ice crystals no place to form. You have probably seen super cooling at work when pulling out a bottle of water from the freezer. By all rights, the water should be frozen, but it isn’t, however, slight impurities or even bubbles can give ice the surface it needs to begin forming. The arctic ground squirrel cleanses its body of nucleators, preventing ice formation. During this time, there is no heart or brain activity, however, it needs to wake several times during the winter, increase its body heat, and then begins to slumber again. It is believed these brief periods of revival are necessary to perform necessary biological activities and maintain electrolyte equilibrium within its cells .
Cold temperatures slow down biological processes so well, lowering the thermostat can effectively prolong the life of many organisms. In the lower, warmer regions of the Baltic Sea, the Arctic clam can live thirty to one hundred fifty years, but in the colder north, it can survive for over five hundred years . I was recently at the 2017 AGE meeting in New York, listening to a lecture by Steve Austad from the University of Alabama at Birmingham. Austad and his colleagues have discovered a remarkable stress resistance in this ocean quohog. If they submerge quohogs in a bath of hydrogen peroxide with related species, the arctic clam will always survive the longest . The creature’s remarkable stress response, and its protein stability, might be why it can live so long in water that often falls below freezing. Extraordinarily, the Greenland shark, also a resident of these cold waters, can survive just as long as the arctic clam . Somewhere out there, there is a heart that was beating at the same time as Shakespeare’s.
Image modified by Philip A. Kramer from original by Julius Nielsen at http://www.bbc.com/news/science-environment-37047168. Text from A Midsummer Night's Dream, by William Shakespeare.
To the lesser extremes of cold, many animals have learned to hibernate, a process referred to as torpor. Many bears, rodents, and even a primate (dwarf lemur), are able to reduce their core temperature and suppress their metabolic activity, respiration, and heart rate for months, eating little to nothing at all during that time .
Unfortunately, humans were not built for such things. We evolved to use our wits to circumvent these environmental extremes. We learned to make fire when it was cold and to preserve our food and carry our water when both were scarce. We are so good at surviving harsh environments, we even figured out how to travel to our Moon and back. So now, medical doctors and researchers are trying to replicate the biology of these unique organisms to make suspended animation possible for humans.
While humans have not evolved to survive cryostasis, examples populate the web of men and women falling beneath the ice of a lake, or getting lost in a winter storm. Many die, but some die and return to life.
“You aren’t dead until you are warm and dead,” goes the increasingly common saying. Some survivors have come back to life hours after their hearts have stopped beating . Now, many researchers and medical professionals want to do it on purpose. Their hope is to give critically injured or severely ill patients a few more hours of life so doctors can implement other life-saving interventions.
In contrast to the norms of science fiction, where ice crystals form around the edges of the stasis pod window and its occupant is solidified in ice, modern medicine can only achieve a suppressed animation. Therapeutic hypothermia is a technique wherein doctors carefully decrease core body temperature to about 85-93 degrees Fahrenheit, a temperature most would still consider warm to the touch. Nevertheless, such a small temperature change vastly decreases the respiration rate, heart rate, and metabolism of cells. Without sufficient oxygen, brain cells can die within five minutes, however, when cooled, the cells do not require as much oxygen, allowing them to survive for much longer periods of deprivation. Therapeutic hypothermia has already shown positive results in reducing the damage caused by injury, strokes, or heart attacks . Drugs that suppress shivering are required while doctors reduce the body temperature with icepacks, cold blankets, and even cold IV fluids. So far, fourteen days is the longest in which doctors have maintained patients in mild therapeutic hypothermia and with no ill effects . Shorter duration hypothermia at temperatures approaching fifty degrees Fahrenheit are in clinical trials. This procedure, emergency preservation and resuscitation (EPR), requires the infusion of large amounts of cold saline directly into the aorta. One day doctors hope EPR will buy time for critical surgical interventions on patients suffering from traumatic injury, stroke, or heart attacks .
While ultra-cold preservation of entire human bodies may not be available in the near future, modern medicine is already doing it with human cells and tissues. Cord blood, bone marrow, and some ovarian and corneal tissues can be frozen and stored for years before thawing and transplantation [21,22]. Hundreds of cell lines sit on liquid nitrogen in biotech companies, waiting their revival for medical research. Millions of sperm and egg specimens wait for the day they can finally meet and make a human life. All of these life-saving (and life-starting) applications use single cells capable of surviving years of cryostasis.
In transplantation medicine, large tissues and organs are much more difficult to preserve. This has led to an entire industry of coordinators, linking potential donors with recipients. Often they will keep a brain-dead donor on life support, to act as an incubator for an organ until the recipient arrives at the hospital and is prepped for surgery. Placing the organs on ice, or even perfusing them with cold buffer, has significantly extended their viability. These organs have not been successfully frozen and then transplanted, but great strides are being made in the field recently . A lack of availability and long-term tissue and organ preservation leads to hundreds of thousands of deaths each year in the U.S. for those in end-stage organ failure [24,25].
So why is cryopreservation so difficult? Why can’t we press the pause button on life as easily as science fiction writers make it sound?
Challenges of Suspended Animation
Without a dramatic decrease in temperature, biological processes remain active, causing problems for long-term stasis. To place cells, tissues, or even an entire human body in stasis for any lengthy period required freezing temperatures. But this comes with its own set of challenges.
While occasionally there are examples of people falling into a frozen lake and being revived hours later, there are no examples of people freezing solid and returning to life . Ice crystals are to blame for that. Even those individuals who survived this accidental suspended animation suffered severe frostbite in their extremities where ice crystals formed in their tissue . You can see this same process occur in meat, vegetables, and fruits that you’ve pulled from your freezer. Vegetables and fruits will have lost their firmness, and meats will be tenderized to a degree.
Membranes, water insoluble lipid barriers, make each of our cells single, viable entities. When these membranes are disrupted, critical electrochemical gradients are destroyed, and cells can no longer dictate what enters and exits. Death quickly follows. The challenge of cryostasis occurs when water arranges itself into crystalline ice. This ice can pierce membranes. Even if membranes remain intact, ice can shear DNA and proteins and displace solutes, artificially concentrating them to toxic levels. An osmotic imbalance can also disrupt electrochemical gradients in cellular organelles, like the mitochondria, which uses a proton gradient to drive the synthesis of ATP, a molecule used by the cell to carry out most enzymatic processes.
Diagram by Martin Chaplin, courtesy Creative Commons.
There are 17 different phases of ice, but most of them only form at the extremes of temperature and pressure that are not compatible with life . Ordinary ice (Ice Ih), like the kind in your freezer's ice tray, is crystalline, and forms when water molecules arrange themselves in a hexagonal shape during a slow freeze. To prevent this dangerous arrangement of ice crystals, suspended animation technology seeks to create a different kind of ice, the kind that forms in space or in extremely low temperatures and pressures. This ice is amorphous, non-crystalline, and does not have the damaging properties of crystalline ice . The process used to make amorphous ice in biological tissues is called vitrification .
Cryoprotectants, can facilitate this vitrification process by preventing the formation of crystalline ice. Some cryoprotectants, such as dimethylsulfoxide (DMSO), can get inside cells and tissues and prevent these ice crystals from forming . But they aren’t nontoxic. One method may be to combine cryoprotectants into a cocktail, gaining their advantageous effects but diluting their dangerous ones.
This brings us to the thawing and resuscitation process. Surprisingly, thawing may be more deleterious than the act of freezing. Doctors grapple with this challenge daily when performing medical research or storing cells for therapeutic use. Even with the most effective cryopreservative solutions, huge percentages of cells are lost during the thawing process. This has cost the medical industry millions in lost revenue by drastically depleting the number of cells they can recover for research and treatment purposes.
Dr. Brian Hawkins, a commercial cryopreservation expert, tells me that there are two major stages of cryo injury. The first occurs during the freezing process itself and can be observed as a large amount of cell death immediately upon thaw. This stage may largely be due to mechanical injury and necrotic cell death, as cells are physically damaged by ice crystal formation or osmotic stresses. The second stage takes place over the following twenty-four hours, wherein cells irreversibly damaged by the freezing process are unable to return to normal function and execute programmed cell death. While the exact causes of cryopreservation-induced delayed onset cell death are still unclear, one potential cause is dysfunctional mitochondrial metabolism and the excessive generation of reactive oxygen species. Oxidant stress can induce a cell death pathway, known as apoptosis, which causes DNA to fragment and the cell membrane to lose its integrity.
“Cryopreservation research historically focused on the physical stresses of freezing, such as ice formation, membrane biology, and solute toxicity,” Hawkins says. “Only recently have scientists started to investigate the biology of low temperature stress at the cellular, proteomic, and genomic levels, as well as the complex biochemical processes needed to keep cells alive during freezing. This is especially true with regards to cellular metabolism and mitochondrial function.”
Dr. Hawkins and his colleagues aim to provide researchers and physicians with the tools required to more efficiently preserve cells, tissues, and organs, and to mitigate cell injury and improve survival in the clinic.
To further complicate our progress toward suspended animation, not all cells are equal. Some, by nature of their unique shape, function, and metabolism, are extremely susceptible to the cold stress. For example, research shows that many hibernating animals lose a huge percent of their neuron’s dendritic spines, which might prove detrimental to the complex thought processes in humans . One of my first jobs in the medical field was to process blood donations into a number of components. Later I worked in a hospital blood bank, typing patient blood and delivering the matching units of blood to nurses. It always struck me that each component of the blood could only be preserved at a certain temperature. Red blood cells could be stored in the refrigerator, but platelets had to remain at room temperature. I learned later that platelets stored at lower temperatures were far more likely to activate, which could be deadly in patients experiencing hypothermia . This disparate effect of cold on different cells in the human body makes suspended animation a challenge.
A common thread in suspended animation techniques is the suppression of metabolism. One researcher at the Fred Hutchinson Cancer Research Center decided to suppress metabolism directly to see if this could induce a state of suspended animation [34,35]. And it worked. Dr. Mark Roth exposed mice to low concentrations of a highly toxic gas, hydrogen sulfide, and they slowed their breathing, heart rate, and lay in a near-death state for hours. After removing the gas, the mice returned to normal with seemingly no ill effects. This gas inhibits the mitochondrial respiration, and while it does not decrease temperature directly, Roth discovered that the core body temperature of the mice also plummeted during the suspended animation. This gas has been shown to be produced endogenously in some hibernating mammals and protects their organs during hibernation [36,37]. Could this be the key to making non-hibernating animals hibernate? Maybe, but it has yet to be validated in larger mammals.
Whatever the technique, suspended animation will make its first appearance on the battlefield or in ambulances, where trained medics infuse a cocktail of anti-shiver, metabolic suppression agents, or additional drugs. This field treatment will help sustain critically injured patents or soldiers using therapeutic hypothermia or emergency preservation until they can be transported to an operating room.
But what happens if the ambulance arrives too late, and the patient dies? Cryogenics may be the answer. Several companies offer cryogenics services. On their websites, they advertise the wonders of the technology: see the future, reunite with family, a fresh start, awaken to a cure, or be revived from whatever killed you. To my knowledge, no cryogenics company can get away with dunking you in liquid nitrogen while you are still alive. Many people willingly participate in this service. They participate despite knowing that future may be very far away. The challenges of reviving a person frozen in this manner will not be easy. First, future technicians would have to repair the problem that resulted in the death of the individual, then they would somehow have to stitch up all the membranes that were ruptured, counteract the oxidative stress, mitochondrial injury, and repair the damaged DNA. Some companies, like the Cryonics Institute, are using whole body vitrification with a cryoprotectant mixture to prevent some of physical damage caused by ice. It may take sophisticated genetic manipulation or the development of more non-toxic cryoprotectant mixtures to make cryostasis a feasible option. This does not bode well for all the people currently frozen. It might be just as likely that high resolution imaging technology will come first, technology capable of scanning the frozen brain and translating it into an in silico model of a brain capable of replicating thought patterns. Either way, when they come out of cryostasis, they may not be the same person as when they went in.
The most anticipated future application of suspended animation technology for space enthusiasts is to send people to distant planets. Right now, there is already a company leading the charge. Over the past few years, SpaceWorks Enterprises, Inc., has received funding from NASA’s NIAC program to get a feasible mockup of a real-life stasis pod running . It is a technology many believe will help get the first astronauts to Mars. Their plan: to keep astronauts in a torporlike state for periods of two weeks to a month. A trip to Mars will take much longer than that, so they intend to have astronauts sleep in shifts. Sound like science fiction? Well you aren’t wrong. SpaceWorks was a consultant for the recent sci-fi movie Passengers, staring Jennifer Lawrence and Chris Pratt.
Image courtesy SpaceWorks.
When I reached out to SpaceWorks for this article, Dr. John Bradford, the President and Chief Operating Officer (COO) of SpaceWorks, was happy to answer my questions. When I inquired about his research in human hibernation, he pointed out that they can’t actually make people hibernate and prefer terms like “human stasis,” “torpor inducing,” and “metabolic suppression.” That said, Bradford admits that they are looking to animals that can hibernate as a source of understanding and inspiration.
“Bears are a great model since their core temperature doesn’t drop to the extreme conditions most hibernators experience,” Bradford says. “They can be in torpor for four to five month periods.” He suggests that in the future, with gene therapy or modification, humans could one day achieve a state of hibernation.
SpaceWorks is still evaluating how long people might be sustained in a low metabolic state. They have a lot of data from current Therapeutic Hypothermia practices, and can try to evaluate what’s happening to the human body over the course of 2-4 days. “Longer periods of up to 14 days have been achieved, but data there becomes much more limited,” Bradford says. SpaceWorks highlights some of the challenges they face in a recent paper describing their proposed method . The most immediate obstacles are bleeding, clotting, infection, and electrolyte imbalances, not to mention the preventing the bone loss and muscle atrophy associated with long-term microgravity.
While they hope to achieve months at some point in the future, Bradford states that even a couple of weeks of suspended animation could solve many medical and engineering challenges of space exploration. “With this technology, a variety of new options can be introduced and applied that address major human spaceflight medical challenges and risk areas such as bone loss, muscle atrophy, increased intracranial pressure, and radiation damage. System-level engineering analysis has indicated significant mass savings for both the habitat and transfer stages. These savings are due to reductions in the pressurized volume, consumables, power, structures, and ancillary systems for the space habitat.”
While this may prove feasible for traveling to Mars. The nearest star system is four point three light years away. The recently discovered seven earth-sized planets in the TRAPPIST-1 system are forty light years away . To reach them will take many lifetimes. So unless huge leaps are made in propulsion systems, stasis technology will need to reduce metabolic activity and all biological functions to undetectable levels, without harm to the astronaut. The alternative is a bulky generation ship, where many generations of people live and die. The unpredictable nature of people, culture, politics on such a ship reduces the likelihood of mission success. Bradford believes stasis is “the key enabling technology that will ultimately permit human exploration to Mars and beyond.”
So far, humanity’s fight against time is a losing one. We still have a lot to learn. Perhaps the greatest instructor will be Mother Nature, who has had a billion years of trial and error to bring about life and keep it living throughout environmental extremes. One thing is certain, if we hope to visit the future, prevent death from injury or disease, or spread across the galaxy, we will need to make huge leaps in suspended animation technology. For scientists and science fiction writers, that future can’t come soon enough.
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Copyright © 2017 Philip A. Kramer
Philip A. Kramer, Ph.D. is a biomedical research scientist specializing in metabolism, oxidative stress, and aging research. He has authored many original research articles in peer reviewed journals. He is also a science fiction writer, and the winner of the 2017 Jim Baen Memorial Award for his short story “Feldspar.” He posts regularly in his science and writing blog (pakramer.com), which promotes the use of accurate science in science fiction.