©2004 by Brian Wowk, PhD

This article is a chapter from the book The Scientific Conquest of Death. It is reproduced here with permission of the author and publisher.

SUMMARY: Clinical medicine is now able to “turn off” people for more than an hour with no heartbeat or brain activity for certain surgical procedures. Scientists are on the verge of being able to preserve individual organs indefinitely by using a new technology called vitrification. Brain electrical activity has been detected in animals rewarmed after seven years of frozen storage. Could human life be preserved in an arrested state for years or decades instead of hours? The prospects are still distant, but some people are already betting that current preservation technology may be good enough to be reversible in the future. Whether they are correct is a legitimate scientific question.

Time travel is a solved problem. Einstein showed that if you travel in a spaceship for months at speeds close to the speed of light, you can return to earth centuries in the future. Unfortunately for would-be time travelers, such spacecraft will not be available until centuries in the future.

Rather than Einstein, nature relies on Arrhenius to achieve time travel. The Arrhenius equation of chemistry describes how chemical reactions slow down as temperature is reduced. Since life is chemistry, life itself slows down at cooler temperatures. Hibernating animals use this principle to time travel from summer to summer, skipping winters when food is scarce.

Medicine already uses this kind of biological time travel. When transplantable organs such as hearts or kidneys are removed from donors, the organs begin dying as soon as their blood supply stops. Removed organs have only minutes to live. However with special preservation solutions and cooling in ice, organs can be moved across hours of time and thousands of miles to waiting recipients. Cold slows chemical processes that would otherwise be quickly fatal.

Can whole people travel through time like preserved organs? Remarkably, the answer seems to be yes. Although it is seldom done, medicine sometimes does preserve people like organs awaiting transplant. Some surgeries on major blood vessels of the heart or brain can only be done if blood circulation through the entire body is stopped [1],[2]. Stopped blood circulation would ordinarily be fatal within 5 minutes, but cooling to +16°C (60°F) allows the human body to remain alive in a “turned off” state for up to 60 minutes [3]. With special blood substitutes and further cooling to a temperature of +3°C (37°F), life without heartbeat or circulation can be extended as much as three hours [4]. Although there is currently no surgical use for circulatory arrest of several hours [5], it may be used in the future to permit surgical repair of wounds before blood circulation is restored after severe trauma [6].

While some biological processes are merely slowed by deep cooling, others are completely stopped. Brain activity is an important example. Brain electrical activity usually ceases at temperatures below +18°C (64°F), and disappears completely in all cases as freezing temperatures are approached [7]. Yet these temperatures can still be survived. In fact, not only can the brain survive being turned off, surgeons often use drugs to force the brain to turn off when temperature alone doesn’t do the trick [8]. They do this because if the brain is active when blood circulation is stopped, vital energy stores can become depleted, later causing death. This reminds us that death is not when life turns off. Death is when the chemistry of life becomes irreversibly damaged.

Specialized surgeries are not the only cases in which the brain can stop working and later start again. Simple cardiac arrest (stopping of the heart) at normal body temperature also causes brain electrical activity to stop within 40 seconds [9]. Yet the heart can remain stopped for several times this long with no lasting harm. Anesthetic drugs, such as barbiturates, can flatten EEG (brain electrical activity) readings for many hours while still permitting later recovery [10]. This prolonged drug-induced elimination of brain activity is sometimes used as a treatment for head injuries [11]. Patients do not emerge from these comas as blank slates. Evidently human beings don’t require continuous operation like computer chips. Brains store long-term memories in physical structures, not fleeting electrical patterns.

Perhaps the most extreme example of brains completely stopping and later starting again are the experiments of Isamu Suda reported in the journal Nature [12] and elsewhere [13] in 1966 and 1974. Suda showed recovery of EEG activity in cat brains resuscitated with warm blood after frozen storage at -20°C (-4°F) for up to seven years.

Reversible experiments in which all electrical activity stops, and chemistry comes to a virtual halt, disprove the 19th-century belief that there is a “spark of life” inside living things. Life is chemistry. When the chemistry of life is adequately preserved, so is life. When the chemistry of a human mind is adequately preserved, so is the person.

Suda’s frozen cat brains deteriorated with time. Brains thawed after five days showed EEG patterns almost identical to EEGs obtained before freezing. However brains thawed after seven years showed greatly slowed activity. At a temperature of -20 C, liquid water still exists in a concentrated solution between ice crystals. Chemical deterioration still slowly occurs in this cold liquid.

Preserving the chemistry of life for unlimited periods of time requires cooling below -130°C (-200°F) [14]. Below this temperature, any remaining unfrozen liquid between ice crystals undergoes a “glass transition.” Molecules become stuck to their neighbors with weak hydrogen bonds. Instead of wandering about, molecules just vibrate in one place. Without freely moving molecules, all chemistry stops.

For living cells to survive this process, chemicals called cryoprotectants must be added. Cryoprotectants, such as glycerol, are small molecules that freely penetrate inside cells and limit the percentage of water that converts into ice during cooling. This allows cells to survive freezing by remaining in isolated pockets of unfrozen solution between ice crystals [14]. Below the glass transition temperature, molecules inside these pockets lock into place, and cells remain preserved inside the glassy water-cryoprotectant mixture between ice crystals.

This approach for preserving individual cells by freezing was first demonstrated half a century ago [15]. It is now used routinely for many different cell types, including human embryos. Preserving organized tissue by freezing has proven to be more difficult. While isolated cells can accommodate as much as 80% of the water around them turning into ice, organs are much less forgiving because there is no room between cells for ice to grow [16]. Suda’s cat brains survived freezing because the relatively warm temperature of -20°C allowed modest quantities of glycerol to keep ice formation between cells within tolerable limits.

In 1984 cryobiologist Greg Fahy proposed a new approach to the problem of complex tissue preservation at low temperature [17]. Instead of freezing, Fahy proposed loading tissue with so much cryoprotectant that ice formation would be completely prevented at all temperatures. Below the glass transition temperature, entire organs would become a glassy solid (a solid with the molecular structure of a liquid), free of any damage from ice. This process was called “vitrification”. Preservation by vitrification, first demonstrated for embryos [18], has now been successfully applied to many different cell types and tissues of increasing complexity. In 2000, reversible vitrification of transplantable blood vessels was demonstrated [19].

New breakthroughs in reducing the toxicity of vitrification solutions [20], and in adding synthetic ice blocking molecules [21],[22] continue to push the field forward. In 2004, successful transplantation of rabbit kidneys after cooling to a temperature of -50°C (-58°F) was reported [23]. These kidneys were prevented from freezing by replacing more than half of the water inside them with vitrification chemicals. Amazingly, organs can survive this extreme treatment if the chemicals are introduced and removed quickly at low temperature.

Reversible vitrification of major organs is a reasonable prospect within this decade. What about vitrification of whole animals? This is a much more difficult problem. Some organs, such as the kidney and brain, are privileged organs for vitrification because of their high blood flow rate. This allows vitrification chemicals to enter and leave them quickly before there are toxic effects. Most other tissues would not survive the long chemical exposure time required to absorb a sufficient concentration to prevent freezing.

It is useful to distinguish between reversible vitrification and morphological vitrification. Reversible vitrification is vitrification in which tissue recovers from the vitrification process in a viable state. Morphological vitrification is vitrification in which tissue is preserved without freezing, with good structural preservation, but in which key enzymes or other biomolecules are damaged by the vitrification chemicals. Morphological vitrification of a kidney was photographically demonstrated in Fahy’s original vitrification paper [17], but 20 years later reversible kidney vitrification is still being pursued.

Given this background, what are the prospects of reversibly vitrifying a whole human being? It’s theoretically possible, but the prospects are still distant. Morphological vitrification of most organs and tissues in the body may now be possible, but moving from morphological vitrification to reversible vitrification will require fundamental new knowledge of mechanisms of cryoprotectant toxicity, and means to intervene in those mechanisms.

If reversible vitrification of humans is developed in future decades, what would be the application of this “suspended animation?” Space travel is sometimes suggested as an application, but time travel – specifically, medical time travel – seems more likely to be the primary application. People, especially young people dying of diseases expected to be treatable in future years would be most motivated to try new suspended animation technologies. Governments would probably not even allow anyone but dying people to undergo such an extreme process, especially in the early days. Applications like space travel would come much later.

Medical time travel, by definition, involves technological anticipation. Sometimes this anticipation goes beyond just cures for disease. After all, if people are cryopreserved in anticipation of future cures, what about future cures for imperfections of the preservation process itself? As the medical prospect of reversible suspended animation draws nearer, the temptation to cut this corner will become stronger. In fact, some people are already cutting this corner very wide.

In 1964, with the science of cryobiology still in its infancy, Robert Ettinger proposed freezing recently deceased persons until science could resuscitate them [24]. The proposal assumed that fatal injury/illness, the early stages of clinical death, and crude preservation would all be reversible in the future. Even aging was to be reversed. This proposal was made in absence of any detailed knowledge of the effects of stopped blood flow or freezing on the human body. The proposal later came to be known as “cryonics.”

Cryonics was clever in that it circumvented legal obstacles to cryopreserving people by operating on the other side of the legal dividing line of death. However 40 years later, as measured by the number people involved and the scientific acceptance of the field, cryonics remains a fringe practice. Why? Probably because by operating as it does, cryonics is perceived as interment rather than medicine. Dictionaries now define cryonics as “freezing a dead human.” Is it any wonder that cryonics is unpopular? It is a failure by definition!

Is this view biologically justified? In the 1980s another cryonics organization, the Alcor Life Extension Foundation, adopted a different approach to cryonics. Under the leadership of cardiothoracic surgery researcher, Jerry Leaf, and dialysis technician, Mike Darwin, Alcor brought methods of modern medicine into cryonics. Alcor sought to validate each step of their cryopreservation process as reversible, beginning with life support provided immediately after cardiac arrest, and continuing through hours of circulation with blood replacement solutions. Leaf and Darwin showed that large animals could be successfully recovered after several hours at near-freezing temperatures under conditions similar to those in the first hours of real cryonics cases [25]. Blood gas measurements and clinical chemistries obtained in real cryonics cases further demonstrated that application of life support techniques (mechanical CPR and heart-lung machines) could keep cryonics subjects biologically alive even in a state of cardiac arrest and legal death [26].

This leaves cryonics today in an interesting situation. It is stigmatized as something that cannot work because the subjects are legally deceased. Yet under ideal conditions the subjects are apparently alive by all measurable criteria, except heartbeat. They are biologically the same as patients undergoing open heart surgery, legal labels notwithstanding. The cryopreservation phase of cryonics is of course not yet reversible. But cryonicists would argue that this does not imply death either because death only happens when biochemistry becomes irreversibly damaged, and “irreversibility” is technology-dependent.

To clarify these issues, cryonicists have proposed the “information-theoretic criterion” for death [27]. According to this criterion, you are not dead when life stops (we already know that from clinical medicine), you are not dead when biochemistry is damaged, you are only dead when biochemistry is so badly damaged that no technology, not even molecular nanotechnology [28], could restore normal biochemistry with your memories intact. By this criterion, someone who suffered cardiac arrest days ago in the wilderness is really dead. Someone who suffered only a few minutes of cardiac arrest and cryoprotectant toxicity during morphological vitrification may not be.

Whether one accepts this information-theoretic criterion or not, the modern cryonics practice of using life support equipment to resuscitate the brain after legal death raises important issues. Among them is the scientific issue that cryonics cannot be dismissed simply by calling its subjects “dead.” Two minutes of cardiac arrest followed by restoration of blood circulation does not a skeleton make. There should be a rule that no one be allowed to say “dead” when discussing cryonics. It is usually a slur that communicates nothing scientific.

Whether cryonics can work depends on biological details of cerebral ischemic injury (brain injury during stopped blood flow), cryopreservation injury, and anticipated future technology. There is much published literature on cerebral ischemia, and a small, but growing body of writing on relevant future technologies [29],[30],[31],[32],[33]. There is, however, very little information on the quality of preservation achieved with cryonics [34],[35]. It would seem logical to look to cryobiologists for this information.

Cryobiologists, professional scientists that study the effect of cold on living things, decided long ago that they didn’t want their field associated with cryonics [36]. The Society for Cryobiology bylaws even provide for the expulsion of members that practice or promote “freezing deceased persons.” The result has been the polarization of cryobiologists into either outspoken contempt or silence concerning cryonics. The contempt camp typically speaks of cryonics as if it hasn’t changed in 40 years. The silent camp doesn’t comment on the subject, and usually follows a “don’t ask, don’t tell” policy about cryonics sympathizers among them. This political environment, plus the fact that most cryobiologists work outside the specialty of organ cryopreservation, makes obtaining informed cryobiological information about cryonics very difficult.

The most important cryobiological fact of cryonics (other than its current irreversibility) is that cryoprotectant chemicals can be successfully circulated through most of the major organs of the body if blood clots are not present. We can conclude this by simply considering that everything now known about long-term preservation of individual organs was learned by removing and treating those organs under conditions similar to ideal cryonics cases. It is generally observed that the quality of cell structure preservation (as revealed by light and electron microscopy) is very poor when there is no cryoprotectant, but steadily improves as the concentration of cryoprotectant is increased (provided toxicity thresholds are not exceeded). Recent years have seen a trend toward using higher cryoprotectant concentrations in cryonics, yielding structural preservation that is impressively similar to unfrozen tissue [35].

Somewhere between freezing, morphological vitrification, reversible vitrification of the central nervous system, and reversible vitrification of whole people, there is technology that will lead medicine to take the idea of medical time travel seriously within this century. Whether what is now called cryonics will eventually become that technology remains to be seen. It will depend on whether cryonicists can manage to outgrow the stigma attached to their field, and develop methods that are validated by more biological feedback and less hand waving. It may also depend on whether critics of cryonics can manage to engage in more substantive discussion and less name calling. The ultimate feasibility of medical time travel is a question of science, not rhetoric.

References

1. Aebert H, Brawanski A, Philipp A, Behr R, Ullrich OW, Keyl C, Birnbaum DE, in: European Journal of Cardiothoracic Surgery (1998, vol. 13), “Deep hypothermia and circulatory arrest for surgery of complex intracranial aneurysms“, pg. 223-229.

2. Ehrlich M, Grabenwoger M, Simon P, Laufer G, Wolner E, Havel M, in: Texas Heart Institute Journal (1995, vol. 22), “Surgical treatment of type A aortic dissections. Results with profound hypothermia and circulatory arrest“, pg. 250-253.

3. Rosenthal E, in: New York Times (1990, Nov. 13), “Suspended Animation – Surgery’s Frontier“.

4. Haneda K, Thomas R, Sands MP, Breazeale DG, Dillard DH, in: Cryobiology (1986, vol. 23), “Whole body protection during three hours of total circulatory arrest: an experimental study“, pg. 483-494.

5. Greenberg MS, in: Handbook of Neurosurgery (1997, 4th edition), “General technical considerations of aneurysm surgery“.

6. Bellamy R, Safar P, Tisherman SA, Basford R, Bruttig SP, Capone A, Dubick MA, Ernster L, Hattler BG Jr, Hochachka P, Klain M, Kochanek PM, Kofke WA, Lancaster JR, McGowan FX Jr, Oeltgen PR, Severinghaus JW, Taylor MJ, Zar H, in: Critical Care Medicine (1996, vol. 24), “Suspended animation for delayed resuscitation“, S24-47.

7. Stecker MM, Cheung AT, Pochettino A, Kent GP, Patterson T, Weiss SJ, Bavaria JE, in: Annals of Thoracic Surgery (2001, vol. 71), “Deep hypothermic circulatory arrest: I. Effects of cooling on electroencephalogram and evoked potentials“, pg. 14-21.

8. Rung GW, Wickey GS, Myers JL, Salus JE, Hensley FA Jr, Martin DE, in: Journal of Cardiothoracic and Vascular Anesthesia (1991, vol. 5), “Thiopental as an adjunct to hypothermia for EEG suppression in infants prior to circulatory arrest“, pg. 337-342.

9. Lind B, Snyder J, Kampschulte S, Safar P, in: Resuscitation (1975, vol. 4), “A review of total brain ischaemia models in dogs and original experiments on clamping the aorta“, pg. 19-31.

10. Bird TD, Plum F, in: Neurology (1968, vol. 18), “Recovery from barbiturate overdose coma with a prolonged isoelectric electroencephalogram“, pg. 456-460.

11. Toyama T, in: Barbiturate Coma.

12. Suda I, Kito K, Adachi C, in: Nature (1966, vol. 212), “Viability of long term frozen cat brain in vitro“, 268-270.

13. Suda I, Kito K, Adachi C, in: Brain Research (1974, vol. 70), “Bioelectric discharges of isolated cat brain after revival from years of frozen storage“, pg. 527-531.

14. Mazur P, in: American Journal of Physiology (1984, vol. 247), “Freezing of living cells: mechanisms and implications“, pg. C125-142.

15. Polge C, Smith A, Parkes AS, in: Nature (1949, vol. 164), “Revival of Spermatozoa after Vitrification and Dehydration at Low Temperatures”, pg. 666.

16. Fahy GM, Levy DI, Ali SE, in: Cryobiology (1987, vol. 24), “Some emerging principles underlying the physical properties, biological actions, and utility of vitrification solutions“, pg. 196-213.

17. Fahy GM, MacFarlane DR, Angell CA, Meryman HT, in: Cryobiology (1984, vol. 21), “Vitrification as an approach to cryopreservation“, pg. 407-426.

18. Rall WF, Fahy GM, in: Nature (1985, vol. 313), “Ice-free cryopreservation of mouse embryos at -196 degrees C by vitrification“, pg. 573-575.

19. Song YC, Khirabadi BS, Lightfoot F, Brockbank KG, Taylor MJ, in: Nature Biotechnology (2000, vol. 18), “Vitreous cryopreservation maintains the function of vascular grafts“, pg. 296-299.

20. Fahy GM, Wowk B, Wu J, Paynter S, in: Cryobiology (2004, vol. 48), “Improved vitrification solutions based on the predictability of vitrification solution toxicity“, pg. 22-35.

21. Wowk B, Leitl E, Rasch CM, Mesbah-Karimi N, Harris SB, Fahy GM, in: Cryobiology (2000, vol. 40), “Vitrification enhancement by synthetic ice blocking agents“, pg. 228-236.

22. Wowk B, Fahy GM, in: Cryobiology (2002, vol. 44), “Inhibition of bacterial ice nucleation by polyglycerol polymers“, pg. 14-23.

23. Fahy GM, Wowk B, Wu J, Phan J, Rasch C, Chang A, Zendejas E, in: Cryobiology (2004, vol. 48), “Cryopreservation of Organs by Vitrification: Perspectives and Recent Advances“, pg. 157-178.

24. Ettinger RCW, in: The Prospect of Immortality (1964, 1st edition), Doubleday & Company.

25. Alcor Life Extension Foundation website: Alcor’s Pioneering Total Body Washout Experiments.

26. Darwin M, in: Biopreservation Tech Briefs (1996, no. 18), “Cryopreservation of CryoCare Patient #C-2150“.

27. Merkle RC, in: Medical Hypotheses (1992, vol. 39), “The technical feasibility of cryonics“, pg. 6-16.

28. Drexler E, in: Engines of Creation (1986, 1st edition), Anchor Press/Doubleday.

29. Darwin M, in: Life Extension Magazine (1977, July/August), “The Anabolocyte: A Biological Approach to Repairing Cryoinjury“, pg. 80-63.

30. Drexler KE, in: Proceedings of the National Academy of Sciences (1981, vol. 78), “Molecular engineering: An approach to the development of general capabilities for molecular manipulation“, pg. 5275-5278.

31. Donaldson T, in: Analog Science Fiction / Science Fact (1988, Sept.), “24th Century Medicine“.

32. Freitas RA, in: Nanomedicine, Vol. I: Basic Capabilities (1999, 1st edition), Landes Bioscience.

33. Freitas RA, in: Nanomedicine, Vol. IIA: Biocompatibility (2003, 1st edition), Landes Bioscience.

34. Alcor staff, in: Cryonics (1984, November), “Histological study of a temporarily cryopreserved human“, pg. 13-32.

35. Darwin M, Russell R, Wood L, Wood C, in: Biopreservation Tech Briefs (1995, no. 16), “Effect of Human Cryopreservation Protocol on the Ultrastructure of the Canine Brain“.

36. Darwin M, in: Cryonics (1991, June, July, August), “Cold War: The Conflict Between Cryonicists and Cryobiologists“.