Cryonics is a branch of Biology, Chemistry and Medicine that deals with the slow down of biological processes for various purposes. These include: cryopreservation of cells and organs for transplantation, cryopreservation of uni- and multicellular organisms for research, and preservation of endangered species. Furthermore, cryonics is used to preserve humans and animals in order to prevent death in cases in which contemporary medicine cannot provide a solution. Advocates of cryonics hope that future medicine could cure (or prevent) most diseases, and that even aging will one day become a disease of the past. The idea of body preservation upon death is not new, dating back to ancient cultures, and relies on the assumption that long-term preservation of the human body is possible without altering the person’s identity. Recent scientific breakthroughs enable the cryopreservation of larger organs for longer times so that they regain vitality after being thawed. Nevertheless, a successful thaw of an entire cryopreserved human body has not been demonstrated yet and it is not clear whether this is even possible. Despite the uncertainty and in the absence of a better alternative, many people have chosen to cryopreserve themselves and as of 2018, 300 people are cryopreserved and 3000 more are registered with a cryogenics service provider that will cryopreserve them after they are declared dead. Some of the people already cryopreserved are young people who have died as a result of a severe disease or an accident. Cryonics could possibly provide them a second chance to experience the life taken from them at such an early stage.
The definitions used to check for vitality signs and declare death have been subjected to many changes throughout history and even from one place to another. Apart from medical considerations, those definitions are influenced by political, social, cultural, philosophical and religious aspects. The variability is often reflected in the choice of the organs according to which vitality is diagnosed, and the minimal duration of organ inactivity after which death can be declared. Thus, definitions that are less strict or based on less indicative vitality criteria, may have led to a premature declaration of death. The accumulation of medical knowledge and the development of diagnostic and resuscitation tools allow us to check for vitality signs more accurately and save people (and other animals) that would not have survived otherwise. This leads to the hypothesis that future emergency medicine could solve many medical cases now considered lethal. This is in addition to preventive or curing diseases before reaching a life-threatening stage. These include early diagnosis of cancer and alzheimer’s, replacement of organs damaged as a result of disease or accident, rehabilitation from severe brain injuries and even halting and reversing aging itself [1,2].
The two most popular approaches to check for vitality signs in the 18th century were centralism and decentralism. According to centralism, there is a necessary and sufficient component for life to exist located in a single organ (conventional wisdom had it that this organ is the heart, mainly due to the observation that the heart can sometimes keep beating after the brain and lungs have ceased functioning). According to the decentralism, the vitality component is located in all tissues and therefore has to be looked for in all of them prior to death declaration. The ability to induce muscle contraction using electrical stimulation after the heart has ceased to beat served as supporting evidence to decentralism. Surgical and resuscitation methods developed during the 18th and 19th centuries contributed to the understanding that organs that shut down could, in some cases, regain full functionality. This observation has led to a decrease in the popularity of centralism . However, the understanding that some organs can be replaced and some not, has strengthened the idea that some organs are more important than others, and in particular the brain, which is irreplaceable, is of utmost importance. Until the 19th century various, somewhat bizarre, techniques were used as criteria for the declaration of death. Among them were: putting a feather or a cotton patch near the nostrils to detect respiration, placing leeches in the anal area, pinching the nipples, or inserting a long needle with a flag at its tip into the heart so that the flag would wave in response to cardiac activity . The fear of misdiagnosis of vitality signs has led to the development of more precise and strict criteria such as using the stethoscope to listen to internal sounds such as that of the heart, lungs and blood flow; the EEG, used to record the brain’s electrical activity; and criteria such as rigor mortis and pulse loss for at least 5 minutes .
Currently, efforts are being made to establish a universal convention to test for vitality signs and for the declaration of death. Yet, those definitions still possess major differences between different Western countries. There is a wide agreement that the criteria for the declaration of death must include the loss of the ability to be conscious, along with the loss of the ability to breath – both controlled by the brain. Based on this agreement, three criteria were established for declaration of death, used together or separately, depending on the medical circumstances: somatic, circulatory and neurological. A review published in 2012 in the British Journal of Anaesthesia specifies the differences in these criteria between the UK, USA, Canada and Australia. The differences are mainly reflected in the minimal duration required to look for vitality signs, the types of tests that must be carried out (and the number of repetitions) and the type and number of specialists that must be present during the procedure . The evolution of these definitions, as well as their variability between different countries, suggest that the decisions involved in death declaration are affected not only by the medical circumstances of the patient, but also by the knowledge, technology and skills available. It is likely that at the moment of death declaration, even according to the most strict criteria, the brain structures that define the person’s identity are still preserved. This is particularly the case when the patient is connected to a life-support system that facilitates the flow of blood throughout the body.
Cryonics is not about resurrecting the dead. Instead, it challenges contemporary definitions used to check for vitality signs and declare death, similar to the changes these definitions underwent over the years together with advances in emergency medicine. The justification for these changes derives from the assumption that, given the appropriate treatment before death declaration (and maybe even minutes or hours later), the biological structures that define the person’s identity can be preserved to allow for full rehabilitation, given the appropriate knowledge and technology. It is important to point out that the term “identity” is not well-defined and is, at least in part, subjective. In fact, a person’s identity constantly changes as a result of her\his experiences. These include changes in the molecular level that affect, for example, the brain’s structure and function. In particular, a person’s identity might change as a result of a traumatic event. In this context, the freezing and thawing procedures can definitely be regarded as traumatic events that will affect, the person’s identity to some extent. Cryonics advocates argue that these kind of changes are negligible. More research is required to develop objective identity tests and in particular such that can be used to quantify identity differences before and after a traumatic event [3,4].
Arriving to the patient on time is critical to artificially maintain blood flow after the body’s systems responsible for this have collapsed. This is crucial to prevent as much as possible cell death, as well as the destruction of tissue structure and the brain’s tissue in particular. Similar to the possibility to resuscitate a person with a heart that ceased to beat, future medicine may be able to perform successful resuscitations in cases in which contemporary medicine fails. Providing the appropriate treatment before and after declaration of “death”, and in particular the freezing procedure, are intended to preserve the person’s body in the best possible condition, and leave the rest of the work to future medicine.
The success of the cryogenic procedure depends not only on the freezing and thawing procedures, but also on the ability to cure the cause of “death” and regaining vitality (consciousness in particular). Among all causes of death, aging is without a doubt one of the most challenging ones. While most diseases and accidents requires a treatment targeting a specific organ, gene or parasite, all the cells in the body undergo aging. However, it is important to note that aging is not a passive, but an active process controlled at the genome, cell and tissue levels. The mutation rate and the rate of metabolism and the accumulation of harmful substances in the cell and tissue, are all controlled processes executed by our body as part of a genetic program shaped during millions of years of evolution [5-10]. In other words, the effectiveness of the mechanisms responsible for keeping the body in shape, is encoded in the genome and dictates the balance between preservation and wear processes. The balance between these two processes changes throughout our lives, as well as across the animal kingdom. For example, the enzyme responsible for DNA replication during cell division (DNA polymerase) makes random mistakes (just as every machine does) that introduce new mutations in the genome. Studies show that the rate of mutation accumulation is inversely correlated with the lifespan of various organisms [11,58]. In addition, terminal genome segments are lost during cell division. These terminal segments constitute genetic sequences called “telomeres”, which do not encode for any important information and mainly function to cap the ends of the chromosomes and protect the rest of the genetic code. In 1984 Carol W. Greider and Elizabeth H. Blackburn discovered the Telomerase: an enzyme responsible for the recovery of the telomeric segment lost during cell division . In 2009 they were awarded the Nobel Prize in Physiology or Medicine for this discovery. Following these findings, the initial telomeric length and Telomerase efficiency (which changes throughout the organism’s life and across species) have been found to be highly correlated with cell death, aging and cancer. As evidence, in 2010 a research group from Harvard has shown that increasing the production of the Telomerase enzyme results in the extension of the lives of mice with a congenital disorder causing them to age faster . However, cell death is also a mechanism crucial for normal life through which the body gets rid of defective cells. Thus, excess of this enzyme is also hazardous and provides a survival advantage to cancer cells [14,15]. The improvement in the understanding of such processes already allows us to develop techniques to control them. This may one day allow us to halt the aging process and even reverse it to a younger state by restoring the preservation-wear balance. In particular, genome editing techniques together with the use of stem cells will allow us to culture personalized organs in the lab and repair irreplaceable tissues [16,54].
The cryogenic process can be divided into two main steps: freezing and thawing. Freezing slows down processes at the molecular level and thus practically slows time down. It is used to keep the body in a condition closest to that prior to freezing. Thus, in addition to freezing and thawing techniques, the freezing temperature and the time during which the organism is under non-physiological conditions are of great significance. There are multiple cryopreservation protocols, most adjusted to the type of organism and in particular its size. One of the greatest challenges in the cryopreservation of living creatures stems from a physical property of water: its volume increases with the decrease in temperature. Since water makes up a large portion of the cell’s volume, freezing causes the destruction of the cell’s membrane and results in cell death. Different methods tackle this challenge using slightly different protocols, but all use cryoprotectant solutions that facilitate the extraction of water from the cells and replacing it with substances which do not increase in volume with the decrease in temperature. However, some of those solutions damage the cells in different ways and there is research currently carried out aiming to minimize this damage.
The first successful cryopreservation of a living creature has been carried out as early as 1663 by Henry Power who managed to cryopreserve Eelworm nematodes in vinegar for several hours and then thaw them back to life [17-19]. The first attempts to cryopreserve bacteria were carried out in the early 20th century, first using liquid air and later using liquid nitrogen [17,20-24]. In 1949 a research group reported a successful experiment for the cryopreservation of avian sperm . In 1960 fungi were successfully cryopreserved and later similar techniques were used to cryopreserve various multicellular organism [26-33]. Interestingly, some animals have their own congenital cryopreservation mechanisms that allow them to survive freezing for months or even years. For example, Rana sylvatica is a frog living in the woods of north america. During the winter it is completely frozen and covered with ice. It survives these conditions using a sophisticated mechanism that allows it to replace the water in its body with glucose and thus avoid ice formation that would otherwise result in the destruction of its cells. This mechanism may be harnessed in the future for the cryopreservation of organs and even whole organisms . In 2018 a research group in Moscow reported the thawing of frozen sediment samples from the arctic region in the north pole. Those samples revealed nematodes (tiny worms living in the soil). Some of those nematodes came back to life after they were thawed without any special treatment. According to carbon dating they were frozen for 42,000 years .
In 2002 Sydney Brenner and John Solston were awarded the Nobel Prize in Physiology or Medicine for their innovative and groundbreaking research in a 1mm long worm named C. elegans. Brenner and Solston, together with John White and others, mapped the entire cell lineage of C. elegans during embryonic development: from the zygote (the fertilized egg – a single cell) to the mature worm made of precisely 959 cells. In addition, they mapped the position and morphology of all the cells in the nervous system and their synaptic connections (i.e. the connectome) [35-38]. In 2002 of C. elegans became the first organism for which the genome was fully sequenced. All this has made C. elegans the most mapped organism in history, a fact that remains true even today. The unprecedented amount of information about a relatively anatomically simple organism, but one that exhibits complex behaviors, serves to this day as an incentive to understand fundamental principles in genetics and neuroscience that can later be applied to humans. In particular – how a genome makes an organism and how a nervous system generates behavior. The high conservation between the worm and human genomes allows us to use the worm as a model for various diseases such as cancer and Alzheimer’s. The research into C. elegans includes the creation of new strains that carry a mutation in a specific gene. Comparing the mutant and normal strains allows us to learn about the function of the gene in question. To preserve new mutant strains for reuse, Solston and Brenner developed a protocol for the cryopreservation and thawing of the worm, a process that quickly became standard: after the creation of a new mutant worm, we let it reproduce for a few days until there are hundreds of worms carrying the same mutation. Then we freeze them within a hypertonic solution (a solution with salt concentration higher than that within the cell) and liquid nitrogen. After hours, days or years those worms can be thawed and those that survive usually restore full and normal functionality as they were prior to freezing [35,39]. In fact, mutants that have been cryopreserved in the ‘70s by Brenner and Solston are still used today. In addition, the CGC (Caenorhabditis Genetics Center) library was established: an international library containing ~40,000 cryopreserved mutant strains. The different strains can be ordered online and sent via mail .
Human sperm and egg are being routinely cryopreserved in -196oC since the ’80s, and can be thawed after many years for in vitro fertilization, among other things [41,42]. However, more research is needed to understand the consequences of the changes these cells undergo as a result of this process, and to increase their rate of survival . Cutting edge science today involves the cryopreservation of larger and more complex organs consisting of multiple types of tissues. The main incentive to invest in this field is organ donation, where one of the primary objectives is to establish an organ bank that will allow us to bridge the gap between supply and demand. One major limiting factor in organ donation is the time gap between organ procurement and transplantation (affected mainly by medical considerations and the distance between the donor and the recipient). Therefore, extending the freezing duration in just a few hours will enable to save many more lives . Between 2014-2017 the DoD (United States Department of Defense) granted about $15 million to 35 research groups for projects aiming to promote the organ banking vision . The main challenge in long-term cryopreservation, that requires extremely low temperatures, is to avoid ice formation during cool-down and warm-up. To achieve this, technologies for fast and homogeneous freezing and thawing are required. This becomes harder for larger and less homogeneous organs (e.g. organs that consist of more types of tissues).
Vitrification is one of the most abundant cryopreservation techniques. In this technique fast cooling is used to transform the tissue into solid state while avoiding ice formation. In 1985 Greg Fahy and Will Rall accomplished the first vitrification of mouse embryos . It was later applied to sperm and egg of other organisms [46,47], but not for larger tissues or organisms. This is due to the difficulty to avoid ice formation and the need to use cryoprotectant substances that are toxic to the tissue. In 2002 Fahy managed to vitrify a rabbit kidney in -130oC, thaw it and then transplant it in another rabbit. He also showed that this rabbit could live normally and specifically that the kidney is functioning normally . While conventional methods allow us to cryopreserve livers for 24 hours only , in 2014 a research group in the US managed to cryopreserve a mouse liver for 4 days using supercooling, and then thaw it and transplant it in another mouse . In 2017 a research group led by John Bischof demonstrated the use of nano-technology for fast and homogeneous heating of large volume tissues. They injected an iron oxide solution to a 50ml (0.05 liter) tissue and vitrified it. They then used radio-frequency laser to excite the iron-oxide nanoparticles. This allowed them to warm-up the tissue at 130oC per minute. This way they achieved fast and homogeneous warm-up and avoided ice formation . Their next goal is a 1 liter tissue . For comparison, the volume of an adult human brain is about 1.5 liter . In Israel, in 2017, Dr. Or Fridman and Professor Amir Arav from the Tel Aviv Sourasky Medical Center were able for the first time to cryopreserve a mouse limb at -80oC using directional freezing, and to thaw it after 30 days and transplant it in another mouse . The scientific achievements throughout history and in the last decade in particular, strengthen the hypothesis that restoring normal functionality after long-term cryopreservation is within reach.
Similar to any other technology and in particular life-saving technologies, cryonics raises some issues and challenges that humanity will have to address. Most are relevant to the era following the awakening of the immigrant from the past from the cryogenic hibernation, but not only.
From the psychological point of view, people will wake up from the cryogenic hibernation to a world very different from the one they are used to, in ways that may be difficult for us to imagine. From their point of view it is an actual time travel as no brain activity exists during cryopreservation and thus the time difference should feel like a few seconds or minutes. In addition, significant medical procedures might be necessary to cure the human body (and maybe even rejuvenate it) and restore consciousness. Beyond the initial trauma, the immigrants from the past will have to integrate into a society that may turn out to be very foreign to them. This may be accompanied by psychological difficulties that humanity is not yet prepared for. To deal with such challenges, the cryonics program has to provide psychological support that includes psychological preparation during the years prior to cryopreservation, as well as after the thaw to help deal with this new reality.
From the financial point of view, it is crucial to make sure that people that enter the cryonics program will be able to make a living when they wake up from cryopreservation. Without the resources needed to access basic services and the ability to purchase basic products, those people will be pushed aside to the margins of society and will find themselves in a constant struggle for survival. The solution for this has to come from the government, the cryonics organization and the person herself\himself. First, the immigrants from the past should be considered citizens in order to be eligible for civil rights and in particular to have access to basic services. However, in certain countries, some basic services (and medical services in particular) are not free. Setting a minimal amount for deposit prior to cryopreservation can secure the future financially. Part of this amount can be invested in insurance that will guarantee the financial coverage of basic services. However, the cryonics organization must do all it can to make its service equally accessible to everyone, and in particular avoid economic discrimination. In addition, the organization should assist and represent its patients and ensure they will have access to all the basic services they require.
From the ecological point of view, cryonics is an additional factor contributing to population growth, a problem that has to be addressed either way sooner or later. Population growth leads to the depletion of resources and overpopulation. In the short term, optimization of urban planning, transitioning to green and renewable energy sources and birth limit may serve as reasonable solutions. In long term, colonizing other planets may be a good solution, once the technology required for such journeys matures. In this context, cryonics is vital for such journeys that may take tens or even hundreds of years.
From the medical point of view, to actualize the cryonics vision humanity will have to overcome significant challenges. Besides cryopreservation and thawing, science would have to find a way to resuscitate people considered dead according to contemporary medicine, and to cure the original reason for carrying out cryopreservation: an accident, disease or aging. The research in cryopreservation of organs for transplantation and for whole body preservation have a lot in common. However, it can be argued that whole-body cryopreservation aiming to extend life, may be contributing to the shortage of donated organs for transplantation. First of all, it is important to bear in mind that the purpose of cryonics itself is to save lives, and that each person gets to decide for herself\himself what to do with their own body (as long as there is no reasonable suspicion for self-harm). Second, recent scientific breakthroughs indicate that we will soon be seeing personalized lab-grown organs (including blood) that can be used for transplantation [54-56]. Finally, those who decide to undergo cryopreservation may choose to preserve their head only, and donate the rest of their organs. This choice is often based on the assumption that all the essential information that defines a person’s identity is stored in the brain, and that in the future all the other organs could be custom-made in the lab (i.e. using the person’s own cells containing her\his own DNA).
From the evolutionary point of view, one can argue that death and birth are essential for natural selection and genetic variation. However, humanity has long ago chosen life over natural selection, and there is no dispute about whether we should cure people when possible. Technologies already in use today allow people to have children that otherwise wouldn’t be born, either due to infertility or premature death of the potential parents. Artificial selection of embryos is already being used to prevent the birth of embryos carrying mutations that would negatively affect their quality of life. Genome-editing technologies that now come into use, allow us to correct mutations in the genomes of both embryos, children and adults . Humanity will have to confront the ethical issues associated with the use of artificial selection and genome-editing aiming to purify and improve physical and mental abilities that are beyond life-saving and suffering prevention.
Despite the challenges posed by cryonics, it is worth bearing in mind that it is a life-saving technology. It is not about resurrection from the dead, but instead aims to postpone death until technology matures enough to deal with medical conditions that contemporary medicine can’t. Even aging, which humanity has learnt to accept with great sorrow, but with no choice, may be regarded in the future as a disease of the past. The role of cryonics is to freeze the hourglass in order to compensate for this technological gap.
There are various reasons for people to choose cryogenics. For many it is simply a survival instinct and an alternative approach to cope with the possibility of losing their loved ones. From this perspective, despite the great deal of uncertainty, cryogenics provides the best chance to save lives. Furthermore, given the opportunity, many people would like to see their children and grandchildren growing up, and to accompany them throughout their lives. Many people would like to have more time for various activities like hobbies and projects they are involved in. When it comes to long-term projects, the motivation to be a part of the whole process and witness its outcome is added. Another dominant reason to choose cryonics is curiosity. What will the world look like in 100 years? 200 years? Which problems will be solved and what new problems will come up? How will future relationships look like? And future politics? Will crime still exist? Gender discrimination? Racism? What will the people of the future eat? What will they do for living? Will a formula for prime numbers be discovered? Will alien life be discovered? Etc. Finally, cryonics gives a chance for those who have not received an equal chance to live their lives due to the inability of contemporary medicine to save them, where fatal accidents and terminal illnesses in children and youth are perhaps the most devastating cases.
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