04. October 2014 · Comments Off on Connectome: How the Brain’s Wiring Makes Us Who We Are · Categories: Cryonics, Neuroscience, Science

Connectome: How the Brain’s Wiring Makes Us Who We Are by Sebastian Seung, Houghton Mifflin Harcourt Trade, 384 pages, 2012.

[This review originally appeared in Venturist News and Views, June-July 2012, 6-7 and Cryonics, September-October 2012]

The scientific perspective that informs Sebastian Seung’s bestselling popular neuroscience book Connectome is so familiar to cryonicists that the bulk of this book could be mistaken for an extensive introduction to the philosophy of mind embodied in cryonics. His book offers a rigorous exposition of the view that our identity is encoded in the connections between neurons, the “connectome,” which itself is shaped by our genes and life experience. The strength of this book is not only its review of the empirical evidence that supports this outlook but its encouraging the reader to think about its implications.  Readers who are intimately familiar with the argument in favor of cryonics should not assume that there is little to learn from this book. As imaging and storage technologies evolve, cryonicists can do more now than in the past to learn about their individual connectome, strengthening the likelihood of successful resuscitation.

One important element of the connectionist premise that structures Seung’s book is that it does not completely resolve competing theories about how the brain works. For example, the recognition that long-term memory (and identity) does not depend on transient electrical activity but has a more robust long-term physical basis that persists during cessation of brain activity (examples are hypothermic circulatory arrest and short periods of cardiac arrest) does not imply a single perspective on how the genome provides the neurological bases for memory formation, retention, recollection, and re-prioritization. One interesting perspective, “neural Darwinism,” which was anticipated by the multi-talented classical-liberal economist Friedrich Hayek, proposes a theory of brain function in which a genetically determined wiring of the brain is subject to competing experiences that strengthen or weaken populations of synapses throughout life. One of the interesting implications of this theory is that consciousness can be treated as an emergent outcome of micro-events in the brain, instead of a mysterious, autonomous property of the brain (think of the curious concept of “free will”).

Seung devotes two chapters to the nature-nurture debate through a connectionist perspective. One of the unfortunate effects of the nature-nurture distinction is that it masks the obvious point that what we call “nurture” (upbringing, environment, etc.) is not exempt from biology but simply concerns the relationship between biological systems and between a biological system and its physical environment. Social scientists who have a strong “nurture”-bias should therefore not be exempted from describing “nurture” in verifiable physical terms, something that many of them do not feel the slightest obligation to do. Another unattractive feature of this debate is that it is routinely portrayed as one between genetic determinists and “environmentalists.” In reality, the debate is mostly between serious scholars who acknowledge that behavior and learning are shaped by both genetics and the environment and those who basically consider the mind a blank slate—a position that is clearly contradicted by existing science but remains popular as a premise in contemporary public policy and certain political ideologies. One of the interesting topics that Seung discusses in these chapters is whether the plasticity of the brain changes over time.

From the perspective of cryonics, the relationship between the genome and the connectome is of great importance. If some of the basic wiring of the brain that encodes personality and temperament is determined by genes and is fixed (or mostly fixed) at an early age, then some parts of the connectome might be inferred from a person’s genome, which opens up an exciting research program for cryonics. A systematic study of the field where genetics meets neurodevelopment might help in understanding the relationship between the genome and brain ultrastructure. This in turn could assist in future resuscitation attempts. To date, the assumption in cryonics has been that the complete ultrastructure of the patient must be preserved (or at least preserved in such a manner that it can be inferred), but if some of it can be inferred from the genome the repair requirements for resuscitation of cryonics patients may be relaxed. Looking for such invariable features in variable brains is an important element of a credible cryonics resuscitation research program.

The power of comparing connectomes is also recognized by Seung in a separate chapter (“Comparing”). There he reviews technologies and approaches to compare connectomes with the goal of understanding personality differences and understanding neuropathologies or “connectopathies.” This chapter is one of several in which the author reviews the existing and emerging technologies that are enabling us to produce a complete connectome, including the innovative equipment of cryonicist and Alcor member Kenneth Hayworth to perform serial electron microscopy. Also discussed are technologies such as diffusion MRI (dMRI), which allows for non-invasive mapping of the connectome at the macro scale using water as a probe. This technology may not be adequate to map the connectome at the cellular level but its contribution to comparative connectomics has already been recognized. It may also hold promise as a means to collect identity-critical information about an individual while alive, which again may lessen the computational challenges involved in cryonics resuscitation. One of the exciting prospects of the field of connectomics is that it can contribute to a further narrowing of the challenges involved in restoring cryonics patients to good health.

Seung closes his chapters on emerging technologies with a review of the prospects of connectomics for the treatment of neurological diseases. One of the potential treatments involves the re-programming of a person’s own (skin) cells to neurons, which can then be introduced in the brain to treat a disease or enhance brain function. Such an approach may also be used to fill the “missing gaps” in the brain of a cryonics patient (alternative technologies include molecular construction of neurons by advanced molecular nanotech­nology).

At this point, I think we can foresee a rather optimistic future for cryonics research and the prospect of resuscitation. Instead of conceptualizing cryonics as the preservation of clinically dead people in the hope that future medicine can restore these people to good health, we can envision a more complex, but more encouraging, path. The work of resuscitation and restoring identity is not something that is expected to occur exclusively in the future but rather will be an ongoing process that starts as soon as the patient is cryopreserved. And with the rise of advanced genomics and non-destructive imaging technologies, some of the initial work can be done while the person is still alive. One of the exciting aspects of being a cryonicist today is that you can take proactive steps to learn about your own connectome and other identity-relevant information.

Seung devotes no less than a whole chapter to human cryopreservation (and the associated idea of chemopreservation). The author recognizes that his own views about the connectome are so similar to the philosophy of mind that underpins cryonics that he needs to do some justice to the rationale of cryonics. One unfortunate aspect is that he situates his discussion of cryonics in the context of religion and immortality. It is undeniable that some cryonicists are motivated by visions of personal immortality but this idea is not intrinsic to cryonics (neither is mind uploading or transhumanism.) Properly conceived, cryonics is an experimental medical procedure that aims to stabilize patients at cryogenic temperatures in anticipation of future treatment. What really distinguishes cryonics from mainstream medicine is not uncertainty (which is a fact of life), but the temporal separation of stabilization and treatment. One regrettable implication of attributing religious motives to people who make cryonics arrangements is that it cheapens the use of the word ‘religious.’ Instead of referring to worship of a higher being, it is here used as a strong belief in something in the absence of conclusive evidence. But by putting the bar so low, Seung (unintentionally) classifies many aspects of life, including choosing novel experimental treatments in mainstream medicine, as “religious.”

At one point Seung writes that research aimed at demonstrating that contemporary vitrification technologies can preserve the connectome will “finally bring some science to Ettinger’s wager.” This is a remarkable statement because even the earliest arguments in favor of cryonics were never presented in the form of a pure wager. In his book The Prospect of Immortality, Robert Ettinger reviews existing evidence from cryobiology and neuroscience and argues that, combined with the expectation that medicine will continue to evolve, the choice to be cryopreserved is a rational decision. Since Ettinger’s book cryonics organizations and wealthy donors have expended a lot of money and time in perfecting preservation techniques and looking at the effects of new technologies on the structure and viability of the brain.  Compared to the state of, let’s say, interventive biogerontology, the scientific progress that has been made in cryonics is not trivial. For example, it is doubtful whether the widespread adoption of vitrification in mainstream cryobiology would have been possible without sustained research into using this approach for complex organs by cryonics supporters. To my knowledge, cryonicists have always been quite eager to generate experimental knowledge to inform their decision making. Now that more advanced technologies to map the human brain are becoming available, cryonics organizations are eager to use them instead of just passively maintaining their “faith.”

Ultimately, Seung still fails to recognize that cryonics inherently involves an element of uncertainty that cannot be eliminated without it not being cryonics anymore (i.e., elimination of uncertainty makes it suspended animation). For example, the author recognizes that it is not necessary for a preservation technology to perfectly preserve the connectome as long as it remains possible to infer the original state (or missing information) from what has been preserved. We can speculate what the limits of such “neural archeology” will be, but I do not think anyone can make conclusive arguments. In this sense, cryonics cannot be completely moved from the realm of informed decision making into the realm of indisputable fact. An element of uncertainty will always be associated with it, even if the experimental evidence in favor of this medical procedure keeps mounting.

The author also discusses alternative preservation approaches such as chemical fixation and plastination. One major disadvantage of existing chemical preservation technologies is that they are irreversible by contemporary techniques (literally a “dead end”) and they do not allow for viability assays to distinguish between worse and better preservation techniques. In contrast, in cryobiology, evidence of good ultrastructural preservation is often a starting point (or independent corroboration) to identify cryoprotectants that are able to store complex organs at cryogenic temperatures and restore them without loss of viability. There is one other formidable challenge that will inevitably arise if chemical preservation is offered as a means of personal survival. It is how to deal with the fact that if chemical fixation is delayed perfusion impairment will prevent complete cross-linking of biomolecules. Even more so than cryonics, chemopreservation requires that the procedure be started prior to, or immediately following, circulatory arrest. In absence of this, the fate of a person’s connectome is uncertain, and may even worsen during storage—a problem cryonics is exempt from.

The book ends with a chapter about mind uploading. One misconception about cryonics is that people seek it as a means to mind uploading, or that reviving the person in a computer is the aim of cryonics. In fact, the late Robert Ettinger became a vocal critic of mind uploading in his final years. He offered a lot of arguments for his skepticism but his main concern was that questions about the feasibility of mind uploading are ultimately empirical questions which cannot be settled by deductive reasoning and dogmatic claims about the nature of the mind or consciousness. One of the amusing aspects of the debate about mind uploading is that proponents and skeptics both accuse the other of not being consistent materialists. Interestingly enough, Seung makes an observation relevant to this debate when he writes how the idea that “information is the new soul” is implied in the mind uploading project.

Despite some misgivings about how Seung presents and conceptualizes cryonics, I am unaware of another book that offers such a clear exposition of the relationship between brain and identity that informs human cryopreservation (and chemopreservation). The most rewarding thing for me was a stronger recognition that the idea of the connectome is not just a premise but opens the door to multiple fruitful research programs aimed at personal survival.

About the Author: Sebastian Seung is Professor of Computational Neuroscience and Physics at MIT and Investigator at the Howard Hughes Medical Institute. He has made important advances in artificial intelligence and neuroscience. His research has been published in leading scientific journals and also featured in the New York Times, Technology Review, and the Economist. (From the dust jacket.)

Dr. Seung was also a speaker at the Alcor-40 conference in October 2012

19. August 2014 · Comments Off on Ultrastructural Signatures of Information-Theoretic Death · Categories: Cryonics, Death, Neuroscience

On October 11, 2013, the Wall Street Journal featured a cover story about the unintended consequences of Norway’s long-time insistence on “plastic graves” (“Grave Problem: Nothing is Rotting in the State of Norway”). You see, after World War II the Norwegians wrapped the dead in plastic prior to burial and now they are faced with…corpses that are not decomposing. Since cemetery real estate is scarce in Norway this creates a rather complicated and sensitive problem. One of the solutions is to poke holes in the ground and plastic to inject a lime-based solution to accelerate decomposition.

Not many people would expect the brains of these plastic-preserved Norwegian corpses to be in pristine condition at the ultrastructural level but this strange story does illustrate that decomposition is a process that is highly sensitive to variables like the presence of oxygen, water, microorganisms, and temperature. Of course, some of these variables are related. When temperatures are lower there will be reduced microbial activity. As a consequence, at cold temperatures the rate of decomposition can be even slower than what one would predict based on the decrease of the brain’s metabolism alone. Cold ischemia is not just warm ischemia slowed down (and vice versa).

My company, Advanced Neural Biosciences, Inc., is currently collaborating with Alcor to produce a series of electron micrographs of brain tissue exposed to very long times of cold ischemia (0 degrees Celsius). One of the reasons we are doing this project is to bring actual data to the decision making process concerning the question when to accept and when no longer to accept a patient who has been stored at low temperatures prior to contacting Alcor for cryonics arrangements.

Ultimately, what we are looking for is an ultrastructural signature of “information-theoretic death.” This presents a formidable problem because information-theoretic death is not an unambiguous identifiable property of an image but concerns our best guestimate about how much structure a future technology might still be able to infer from a given state of damage. For existing patients and members who want to be preserved under any conditions this is not a directly relevant question (the future will tell). But when you have to make a decision whether to accept a third-party “post-mortem” patient, arbitrary decisions have to be made because Alcor simply cannot accept every case brought to its attention.

We have now produced electron micrographs of up to 1 month of cold ischemia. When we shared these 1 month images with the Alcor Research and Development committee one member remarked that he “would not have guessed that so much structure could remain after one month.” When we presented an image from this series at a recent conference, attendees were also surprised about this level of preservation.

Of course, this is not the end of the story because a patient with such a long period of cold ischemia will still need to be cooled to cryogenic temperatures for long-term care and a “straight freeze” on top of such extensive ischemic damage could tip the balance towards informationtheoretic death. These results raise one interesting possibility, however. If the damage of a straight freeze is a lot worse than the damage from moderate times of cold ischemia, cryoprotecting the brain (or both hemispheres separately) by soaking it in cryoprotectant could be a superior protocol for a select number of Alcor cases. There is still much to be learned.

Originally published as a column (Quod incepimus conficiemus) in Cryonics magazine, November, 2013

26. November 2013 · Comments Off on Interview with Aschwin de Wolf · Categories: Cryonics, Neuroscience, Science, Society

[This interview was originally published in Cryonics magazine September 2013]

By Stephen Cave

This magazine generously reviewed my book Immortality: The Quest to Live Forever and How it Drives Civilization in the November/December 2012 edition. But the reviewer argued that I didn’t properly understand cryonics — so I decided to speak to a leading expert. This interview, with Cryonics Magazine’s editor Aschwin de Wolf, is the result. Parts of the interview appeared originally in Aeon Magazine (http://www.aeonmagazine.com)

What is cryonics?

(Stephen Cave) Cryonics is sometimes described as “medical time travel” – is that how you see it?

(Aschwin de Wolf) Yes, that is a good characterization. What sets cryonics apart from other medical procedures is not uncertainty (which is an element of many experimental medical treatments) but the temporal separation of stabilization and treatment. Cryonics reflects the recognition that a disease considered terminal today might be treatable in the future.

Does/will cryonics work?

What is the largest (or most complex) organism (or tissue) that has been successfully cryopreserved and revived (or reversibly vitrified)?

A rabbit kidney has been vitrified and successfully transplanted with long-term survival. Another major achievement that supports the practice of cryonics is the successful vitrification and functional recovery of rat hippocampal brain slices.

In terms of whole organisms, tardigrades and certain insect larvae have been successfully recovered after cryopreservation at low sub-zero temperatures.

What breakthroughs in cryopreservation are still required? When do you think they might come?

Recovery of organized electrical activity in the whole brain (EEG) after vitrification and rewarming would provide further support for the practice of cryonics. This may be achieved in about 5 to 10 years. Long term, the aim should be true suspended animation of a mammal.

It is important to recognize, however, that the damage associated with today’s cryonics procedures only excludes meaningful future resuscitation if the original state of the brain cannot be inferred. Damage-free cryopreservation would be sufficient but it is not necessary to justify practicing cryonics today.

Cryonics depends upon faith in technological progress and social stability (such that well-disposed scientists and physicians in the future will be both able and inclined to revive cryonics patients). Why do you believe the future will be so utopian?

In my opinion, it is more reasonable to ask why anyone would make decisions on the premise that medical progress would come to a screeching halt. Cryonics patients have time, and successful resuscitation does not necessarily require fast or accelerated progress. Cryonics does not rest on an utopian, but on a very conservative, premise.

Resuscitation of cryonics patients is the foremost responsibility of a cryonics organization. That is why organizations like Alcor set aside substantial amounts of money in a separate trust to allow for the maintenance and eventual resuscitation of the patient.

Social acceptance

Why do you think cryonics is not more popular?

It would be tempting to say that cryonics is not more popular because most people do not think it will work. The problem with this explanation is that hundreds of millions of people believe in all kinds of things for which there is no strong empirical evidence at all, such as astrology. In addition, when faced with a terminal prognosis people have a really low threshold for believing in the most implausible treatments.  If the popularity of cryonics would be a function of its scientific and technical feasibility, we should have seen major increases in support when new technologies, such as vitrification, were introduced.

The most likely explanation, in my opinion, is that people fear social alienation and solitary resuscitation in an unknown future. In fact, writers such as Arthur C. Clark, who strongly believed that cryonics will work, personally admitted as much. This is a real challenge for cryonics organizations but there is a growing interest in topics such as reintegration of cryonics patients.

Do you think there might be a tipping point in its popularity? What might bring such a tipping point about?

Scientific and technological breakthroughs in cryobiology (suspended animation) and cell repair will certainly help, but if fear of the future holds most people back there may not be such a tipping point. It is possible, however, that in certain demographical groups making cryonics arrangements will be recognized as the normal, rational, thing to do. Something like is already happening in subcultures that are interested in human enhancement or reducing bias in decision making.

Do you think there will be a day when cryonics is the normal procedure for treating those with diseases incurable by contemporary medicine?

Yes, or at least some kind of long term stabilization procedure will be used for people that cannot be treated by contemporary medicine. I find it hard to imagine that people will persist in burying or burning a person just because there is no treatment today. That is just irrational and reckless.

Philosophy and legal status of cryonics

Are those who are currently cryopreserved, in your view, actually dead?

No. But I do not think we can just claim that they are alive in the conventional sense of the word either, although that may change if we can demonstrate that cryopreservation can preserve viability of the brain.

If not, what state do you consider them to be in?

If the original state of the brain, what some scientists call the “connectome,” can be inferred and restored, cryonics patients are not dead in a more rigorous sense of the word. Their identities are still with us in an information-theoretical sense.

What legal status do you think those who are cryopreserved should have?

They should have much stronger legal status than the deceased have today. While a meaningful philosophical/technical distinction could be made between conventional patients and cryonics patients I think we need to err on the side of caution and give them the same kind of protection as other patients with terminal diseases.

At the very least, obstacles to conducting good human cryopreservation in hospitals should be eliminated because a lot of reservations people have about cryonics are not intrinsic features of the procedure but the results of cryonics organizations being forced to practice cryonics as a form of emergency medicine.

When should it be legal for someone to have themselves cryopreserved (eg, any time? when diagnosed with a terminal illness? or only when brain-dead according to current definitions? etc)

If a patient has been diagnosed as “terminal,” that is basically an admission of the physician that (s)he has exhausted contemporary medical treatment options. At that point it is prudent to identify other means of saving the patient’s life, including stabilizing them at lower temperatures for future treatment. This is particularly important if the patient is in a condition where continued metabolism will progressively destroy the brain. Such a procedure would be the opposite of assisted suicide because its aim would be to preserve life, not to end it.

Ethical considerations

The overpopulation problem: if a few generations of people do all have themselves cryopreserved, then when technology permits them to be revived and healed, will there not be an enormous population boom? How will this be managed?

There are several responses to this question. The most obvious one is to draw attention to the fact that today’s socio-economic debates in the West are about the consequences of a decline in population in the future as a consequence of people having fewer children.

It is also important to recognize that cryonics does not operate in a sociological, psychological, and technological vacuum. If support for the procedure changes so will our views on reproduction and sustainability.

Of course, it should not even be assumed that future generations will be confined to one planet (Earth). 

What do you say to the idea that death gives meaning or shape to life?

Cryonics is not a permanent cure for death. There may always be catastrophic events that could irreversibly kill a person or whole populations. In fact, it may never be possible to know that we will not die for the simple fact that this would require absolute knowledge about the infinite future.

Having said this, no, I do not think that death gives meaning to life. That is just an admission that the things that matter do not have intrinsic value but are experienced with mortality as a framework. Neither introspection nor observation of ordinary life suggests this.

In fact, I suspect that short human life-spans have an adverse effect on morality because it fosters instant gratification and indifference about long-term reputation and/or consequences.

On the other hand, do you think we are morally obliged to practice cryonics (as we might be to try to prolong life in other ways)?

My qualified answer is “yes.” If we believe that the aim of medicine is to preserve life and reduce suffering, cryonics is a logical extension of this thinking. Cryonics is not only a rational response to the recognition that science and technologies can evolve, but it also can be important to stabilize devastating cases of acute brain trauma.


When did you first become interested in life-extension technology?

In my case, my interest in life extension was a consequence of making cryonics arrangements.

When did you first hear about cryonics? When did you sign up for it?

I first read about cryonics on the internet in the mid-1990s. The idea seemed quite reasonable to me but I did not consider it as something that had direct personal relevance to me at the time. This changed in 2002 when a rather trivial medical condition prompted me to think more seriously about my remaining life and mortality. I read a lot of cryonics literature in a short period of time, attended the Alcor conference that autumn, and finalized making cryonics arrangements in January 2003.

Do you proselytize among friends and acquaintances? Have you had much luck in persuading others to sign up for cryonics?

Unless I know that a person has a strong interest in making cryonics arrangements, I generally do not explicitly try to persuade them. This is partly because I do not want people to get defensive in response to the idea. In cases where I know that the person is very open to cryonics, I put more effort into it. I think I have been successful in persuading around 4 people to make cryonics arrangements. There may be more that I am unaware of because of all the writing that I do.

Are you pursuing life-extension practices in the hope that you won’t need to be cryopreserved?

Yes. As most people with cryonics arrangements, I have a strong interest in life extension and rejuvenation research. I am not very optimistic about short-term breakthroughs so I try to eat healthy, exercise, and avoid dangerous activities and excessive stress.

What is your educational background?

I graduated in political science at the University of Amsterdam and have a strong interest in economics and philosophy as well. Over time my academic interests have mostly shifted to biology and neuroscience – also because of the experimental research that I am involved in.

What is your involvement with Alcor or other cryonics institutes/firms?

I have been an Alcor member for 10 years and have been employed in cryonics either as an employee or on a contract basis since 2004. My main activities right now are to conduct neural cryobiology research in my lab at Advanced Neural Biosciences and to edit Alcor’s monthly magazine, Cryonics.

I have always had a good relationship with the other major cryonics organization, the Cryonics Institute, too. In fact, without its support, and its individual members’ support, our research would not have been possible.

What would be your best guess for the year when you will be revived by the scientists of the future? What might the world look like then?

I do not think that there is a uniform year for all cryonics patients. Much will depend on the condition of the patient and prevailing technologies and capabilities at the time. For a typical patient, I doubt we are going to see meaningful resuscitation attempts before 2075.

If the past is any guidance, the (far) future will be a combination of things that have always been with us and things we cannot even imagine right now. I suspect that the most characteristic change in the future will be a seamless integration of human technology and biology and greater control over the aging process. 

04. October 2013 · Comments Off on Resuscitation Research Can Start Now! · Categories: Cryonics, Neuroscience

A major obstacle to strengthening the case for cryonics is the perception that meaningful research aimed at resuscitation of cryonics patients cannot be done today. Attempts to be more specific than evoking the need for a technology that can manipulate matter at the molecular level are considered to be vague and unproductive. Clearly, such a stance is an open invitation for skeptics to claim that cryonics advocates have not much more to offer than hope and optimism. Nothing could be further from the truth. Not only is there a lot of relevant empirical research that can be conducted today, a focused investigation into the technical and logistical challenges of resuscitation can also define cryonics research priorities and refine the stabilization and cryopreservation procedures that we use today.

The first thing that needs to be recognized is that if we want to say something specific about the nature and limits of repair we need to be able to characterize the damage in detail. There has been a lot of general discussion of damage but there have been few writers that have systematically characterized the forms of damage that can occur prior to and/or during cryopreservation and then linked those forms of damage to contemporary or envisioned repair strategies. A notable exception is the 1991 article “‘Realistic’ Scenario for Nanotechnological Repair of the Frozen Human Brain” where the individual forms of mechanical and biochemical damage (ice formation, protein denaturation, osmotic damage etc.) are catalogued and repair strategies are discussed in biological terms.

Describing the various forms of damage at such a detailed level provides a meaningful context within which to discuss the technical feasibility of cryonics in rather specific terms, too. If someone would claim that cryonics is hopeless because of the “toxicity” of the vitrification agents we can ask for more specifics about what kind of biochemical damage is being alleged and why such alterations irreversibly erase identity-critical information.

Even when it is admitted that theoretical and empirical investigations into damage associated with (crude) cryonics technologies is possible it surely would be preposterous, wouldn’t it, to claim that repair of the damage itself can be done today. Well, not quite. Granted, we do not have the biological or mechanical cell repair technologies that would be required for repair of the brain at the molecular level but we can simulate a specific kind of damage (ice formation, ischemia) and create three dimensional neural wiring maps that can be compared to controls. Often this is not even necessary because we understand the universal language of biology and, for example, if we observe a ruptured cell membrane wall we know how it is supposed to look.

From here it is a short step to what I would call “reconstructive connectomics,” a sub-discipline of the field of connectomics that studies pathological changes of neural connections in the brain with the aim of in silico repair. Computational limitations currently constrain the scale and complexity at which we can do these reconstructions but it is not necessary to do reconstructive connectomics in a human-sized brain to obtain a much greater understanding of the mechanisms of damage, the type of repair required, and the empirical content of concepts like information-theoretic death.

It is important to point out here that the idea that resuscitation research can start today does not require taking sides in debates about the relative merits and limitations of biological versus mechanical cell repair technologies. The primary objective here is to show that meaningful resuscitation research can be done today and that the absence of such research only provides our critics easy targets.

Originally published as a column (Quod incepimus conficiemus) in Cryonics magazine, May, 2013

14. January 2013 · Comments Off on In praise of cold · Categories: Cryonics, Neuroscience, Science

Some observers believe that cryonics advocates are reluctant to subject their theories to experimental scrutiny because this could damage their (uncritical) belief in future resuscitation. Similarly, one might think that cryonicists would react with a mix of hostility and dismissal to alternative strategies for personal survival. Nothing could be further from the truth. In fact, it is exactly because our personal survival is at stake that forces us to be wary of dogmatism.

For this reason, I have always been interested in chemical fixation as a (low cost) alternative for cryonics. In fact, years before all the talk about the “connectome” and “plastination” I spent considerable time exchanging messages with Michael Perry at Alcor about the technical and practical feasibility of chemical brain preservation. But no matter how open minded I tried to be about this approach, I kept running into the same challenges over and over again.

The challenge that has concerned me the most is whether a delayed start of chemical brain fixation will produce incomplete distribution of the chemical fixative in the brain because of ischemia-induced perfusion impairment. Thinking about the technical problem of “no-reflow” is not the first thing on the mind of someone who first hears about the idea of using chemical fixatives to preserve the brain. In my case, this concern was not just “theoretical.” In my lab I have spent many years looking at the effects of cerebral ischemia on cryopreservation and chemical fixation. Last year we decided to broaden our investigations to delayed chemical fixation and we have not been pleased at what we have observed so far. After 1.5 years of room temperature storage the delayed aldehyde fixed brains are falling apart and continue to decompose. In small animals one might imagine that such perfusion impairment could be overcome by immersing the brains in the fixative instead but human brains are simply too large. By the time that the fixative would have reached the core of the brain, extensive autolysis will have occurred.

Another complex problem is to identify a fixation and polymerization protocol that fixes all identity-critical parts of the brain. If aldehydes do not completely fix the lipids in the brain, should we add strong oxidizing heavy metals to stabilize lipids? This is possible in theory but, as a general rule, these chemicals are either very expensive or dangerous to use (or both). Even if we are able to identify a chemical fixation protocol for the brain that can do the job, how can we know that such brains are stable for very long periods of time? Should we follow fixation by embedding with a polymer to inhibit residual biochemical activity? To my knowledge, there is no known embedding protocol that is scalable to human brains due to the extreme viscosity of these plastics.

Recently these issues took a more personal nature for me when I had to think really hard about a reasonable but affordable longterm preservation protocol for a companion animal. I spent many days reading the electron microscopy and fixation literature to come up with a protocol that was better than aldehyde fixation and low temperature storage. Adding calcium to the fixative? What about phenol? Post-fixation perfusion of a viscous cryoprotectant to allow storage at subzero temperatures? That is when I really started appreciating the “magic” of cold temperatures.

Absent a vitrification agent, cryogenic temperatures can cause extensive damage to cells. But one thing we know: whatever the nature of this damage, as soon the brain is below the glass transition temperature of -130°C, all water is either frozen or a vitrified rigid solid. We do not have to worry about any damage getting worse over time, or whether some biomolecules have not been fixed. Cold may be “crude” in its effects but it is exactly because no biochemical process can escape inhibition at very low temperatures that makes it such a powerful personal survival technology.

Originally published as a column (Quod incepimus conficiemus) in Cryonics magazine, January, 2013

25. July 2012 · Comments Off on First symposium on cryonics and dementia · Categories: Cryonics, Health, Neuroscience

The recent symposium on cryonics and brain-threatening disorders was a major success. On Saturday, July 7, 2012, around 30 people attended the first ever symposium on dementia and cryonics in Portland, Oregon. The symposium started with a brief introduction by Institute for Evidence Based Cryonics President Aschwin de Wolf, who emphasized why people with cryonics arrangements have a clear interest in understanding and avoiding dementia. The first speaker, Chana de Wolf, introduced the audience to the topic of adult neurogenesis, the two areas in the brain where it occurs, and how little we still understand about it. Aubrey de Grey then talked about the SENS approach to rejuvenation and how some emerging damage repair bio-technologies might be able to also reverse neurodegenerative diseases such as Alzheimer’s disease. Cryonics Institute President Ben Best followed Aubrey’s presentation with a technical introduction about the pathophysiology of Alzheimer’s disease and the treatments that are currently being investigated. Ben is maintaining a page about the molecular mechanisms of Alzheimer’s disease on his personal website.

After the break Alcor staff member Mike Perry presented a detailed analysis of a recent paper in which cerebrospinal fluid samples could predict the onset of Alzheimer’s diseases many years before the first signs of cognitive impairment, a finding that holds great promise for life-extensionists, and those with an increased risk for Alzheimer’s disease in particular. Institute for Evidence Based Cryonics Board member Keegan Macintosh then presented a rigorous legal analysis of the Thomas Donaldson case and indicated how the case could have been argued more persuasively then and now. The last speaker of the day was Alcor President Max More who introduced the concept of the extended mind and its relevance to cryonics and neurodegenerative diseases, which prompted a useful exchange about the desirability of cryonics organizations facilitating members to store identity-critical information. The official meeting ended with a panel discussion moderated by Aschwin de Wolf in which all the speakers took questions from the audience and other speakers.

The program and panel left ample time for interaction between speakers and the audience. The topic of avoiding dementia and what to do when a cryonicist is diagnosed with a brain threatening disorder received a lot of attention. Despite the rather disturbing subject of the symposium there seemed to be a general recognition that it was extremely valuable to explore this topic in the context of cryonics. Some suggestions of how to deal with dementia were made that had not been previously discussed in cryonics publications.

It is not likely that we will organize a symposium about this topic every year but there was a strong interest in organizing meetings about other topics on a regular basis in the Pacific Northwest.

The slides of all but one of the presenters are available on the symposium page and a video recording of Aubrey de Grey’s talk was made by one person in the audience. A more detailed report of the symposium will appear in an upcoming issue of Alcor’s Cryonics magazine.

20. June 2012 · Comments Off on Chemopreservation in the real world · Categories: Cryonics, Death, Neuroscience

It is generally not the task of scientists to consider the legal, financial, and logistical limitations when searching for biomedical breakthroughs but there are good examples where considering the real-world applications of a technology can be instructive. Research aimed at preservation of brains (or the “connectome”) is such an example. Even if chemopreservation can be demonstrated to preserve the intricate wiring of the brain, it can be safely assumed that there will not be a massive change in demand for brain preservation technologies (especially if the technology is too strongly tied to mind uploading). As a consequence, providers of chemopreservation will most likely operate in the same environment as providers of cryonics. That means that, as a general rule, there will be a delay between pronouncement of legal death and the start of procedures.

There is now more than 40 years of mainstream biomedical research demonstrating that even short interruptions of circulation (under normothermic conditions) can produce perfusion impairment in the brain. As has been demonstrated by cryonics researcher Mike Darwin and my own lab, Advanced Neural Biosciences, this “no-reflow” can produce poor distribution of cryoprotectants (including vitrification agents) and associated freezing. One serious concern that cryonics researchers have about chemopreservation-in-the-real-world is that poorly chemically fixed brains will be prone to autolysis during long-term storage. This limitation of chemopreservation applies to both “conventional” biological resuscitation scenarios as to whole brain emulation. One can only recover (or “upload”) what is preserved – or can be inferred. And as far as we understand things today, the advantage of temperature as a long-term preservation method is that it does not depend on a healthy, non-ischemic circulatory system. Cryopreservation of an ischemic brain can produce ice formation, but as soon as it is placed in liquid nitrogen, cold will “fix” whatever there is without further degradation. The same thing cannot be said about chemopreservation under poor conditions.

There is an understandable tendency to compare brain preservation protocols under ideal conditions and favor the method that produces the best preservation. But support for either technology cannot be solely based on results produces under controlled lab conditions. Personal survival technologies should be evaluated under conditions that are most likely to be encountered by organizations that will offer them. Demonstrating that chemical fixation (and plastination) can preserve the connectome is a laudable goal but the case for chemopreservation as a clinical experimental preservation method requires a persuasive response to the objection that delays in fixation can frustrate the aims of chemopreservation in the most fundamental manner.

One interesting aspect of the cryonics vs chemopreservation debate, though, is that it appears that some people simply feel more comfortable with one of the approaches. People who have shown the slightest interest in human cryopreservation can get really excited about the idea of chemical brain preservation. This indicates that if both approaches would be pursued actively, the growth of chemopreservation would not necessarily be at the expense of cryonics but there would be a growth in the total number of people making bio-preservation arrangements aimed at personal survival. But as Mike Darwin has recently pointed out, chemopreservation is not at the stage where it can be responsibly offered. The growth of this field requires a committed group of individuals who will research, develop, and implement this program. Chemopreservation does not need to be perfected before being offered (neither was cryonics) but so far most advocacy has been mostly at the conceptual level.

01. March 2012 · Comments Off on Alzheimer’s disease and cryonics · Categories: Cryonics, Neuroscience

Conventional wisdom in life extension circles is that making cryonics arrangements allows one to benefit from rejuvenation technologies that are not available during one’s existing lifespan. Aside from the risk of high-impact accidents or getting lost at sea, there is one challenge that some cryonicists will face when they grow older; the debilitating consequences of brain-threatening disorders.

One of the unfortunate effects of the increase in human lifespan is a corresponding increase in late-onset identity-destroying brain disorders. We know that some patients at the existing cryonics organizations were cryopreserved after advanced Alzheimer’s disease. Some cryonics organization members who developed Alzheimer’s disease were not preserved at all, due to lapsed insurance and/or cryopreservation arrangements.

The growing awareness that brain-threatening disorders can present a formidable challenge to personal survival is the theme of the latest issue of Alcor’s Cryonics magazine.

To further draw attention to this topic and generate more knowledge how to prevent and treat brain-threatening disorders, the Institute for Evidence Based Cryonics and Cryonics Northwest will organize a symposium on cryonics and brain-threatening disorders on Saturday July 7, 2012, in Portland, Oregon.

Talks include Aubrey de Grey on The SENS approach to repairing the aging brain, Chana de Wolf on neurogenesis in the adult brain and Alzheimer’s disease, Ben Best on drugs, supplements, and other treatments to mitigate and prevent Alzheimer’s disease, Mike Perry on (early) diagnosis of Alzheimer’s disease, and Max More about survival, identity, and the extended mind. Entrance to the symposium is free. More information about the program and registration will be provided soon.

05. August 2011 · Comments Off on ApoE4 – The Ancestral Allele · Categories: Health, Neuroscience · Tags: , , , , , , , ,

Reportedly, when James Watson and Steven Pinker had their genome sequenced, they declined to know their risk for Alzheimer’s disease. Clearly this is not an option for life extensionists and cryonicists, who are better off knowing whether they have a copy or, worse, two copies of the ApoE4 gene.

Patri Friedman, son of the libertarian economist David Friedman (who in turn is the son of the Nobel laureate Milton Friedman), recently learned that he has two copies of the ApoE4 gene when 23andMe updated their reports. Caucasian and Japanese carriers of two E4 alleles have between 10 and 30 times the risk of developing Alzheimer’s by 75 years of age, as compared to those not carrying any E4 alleles. Patri is a life extensionist, practitioner of the paleo diet, and recently made cryonics arrangements with his whole family at Alcor – and is thus far more prone to a pro-active course of action.

When he realized that there was no good central resource for people with copies of the ApoE4 gene he started a new blog called ApoE4 – The Ancestral Allele, which aims to share practical information and research for health-conscious E4 carriers. The first posts discuss some of the benefits of having the E4 gene (better episodic memory) and what kind of diet is recommended for E4 carriers. He also encourages guest posts and other co-bloggers to help run the website.


Ongoing legal challenges and hostile interference of relatives have increased awareness among cryonicists that addressing the likelihood that one will be cryopreserved at all should take center stage among other strategies for survival. As a consequence, a number of individuals have recently taken on the task of working out the conceptual and legal challenges to minimize hostile interference (for a contribution on the ethical aspects of cryonics interference, look here).

One aspect of cryonics optimization planning that has received little attention to date is to develop legal strategies to deal with medical and legal issues surrounding one’s death, terminal illness, and the dying phase. In this memo I will outline some of the most important medical and medico-legal issues, how cryonicists could benefit from recognizing them, and suggest some legal and practical solutions. Before I get to the substance of these issues I would like to briefly identify all the stages in which proactive cryonics planning can improve our odds of personal survival.

Opportunities for cryonics optimization

The first and most obvious decision is to make cryonics arrangements. Alcor members face complicated decision making because the organization offers both whole body cryopreservation and neuro cryopreservation. From the perspective of cryonics optimization many members choose neuropreservation because it enables the organization to exclusively focus on what matters most; the brain. There is also a logistical advantage. In case transport of the whole body across state lines is delayed the isolated head can be released in advance as a tissue sample. Additionally, a number of Alcor members have recognized that it is possible to have the best of both worlds and combine neuro-vitrification and separate cryopreservation of the trunk. This allows the member to take advantage of the superior preservation of the brain that is available for neuro patients without having to forego whole body cryopreservation. This option is not widely advertised so one is encouraged to contact Alcor about revisions in funding and paperwork.

The other obvious decision is to have secure funding in place. Many members have given extensive thought about funding mechanism and wealth preservation so there is little need to discuss this here. From the perspective of cryonics optimization it is important to emphasize the importance of over-funding your cryopreservation. This not only protects you against future price increases, but also enables you to take advantage of technical upgrades that cannot be offered at the current preservation minimums. Another aspect to consider is leaving money to cryonics research. Although it is reasonable to expect that general progress in science will include general cell repair, there may be areas that will only be pursued by those who have a scientific or personal interest in resuscitation of cryonics patients. As in many areas in life, diversification is key. One should not solely depend upon Alcor or CI for successful resuscitation research or efforts.

Another important opportunity for cryonics optimization is to recognize the importance of proximity. From a technical point of view, there is simply no comparison to de-animating near the cryonics facility of your choice. This is not just a matter of reducing ischemic time. Remote standby and stabilization is a fertile ground for all kinds of logistical and legal complications. Most cryonics members do recognize the importance of reducing transport times but it is an established fact that as soon people become terminally ill they become more resistant to the idea of relocating and often prefer to die among friends at home. It is important to anticipate this scenario and to not delay relocation plans until the last minute. Another advantage of relocating at an earlier stage is that one is better protected in case of a terminal disease with rapid decline or sudden death.

As mentioned above, one issue that is getting increasing attention is how to protect oneself against hostile relatives and third parties. The take-home message is to alter cryopreservation contracts and your paperwork in such a matter that there is an incentive *not* to interfere.

Last but not least, something should be said about community building. Cryonicists can greatly benefit from becoming active in their local cryonics group. Often these meetings are open to members of all cryonics organizations. Most cryonics groups organize standby and stabilization trainings where members can familiarize themselves with the basics of the initial cryonics procedures. Such groups may not only play a part in your own future cryopreservation but are also useful to get a basic understanding about what you can do in the case a local member or a loved one needs to be cryopreserved. Another important aspect of participation in a local cryonics group is that one remains in contact with other cryonicists. When people get older their friends and family members die and the member has little communication with those who are aware of his desire to be cryopreserved. If you live in an area where there are no local cryonics groups contact your cryonics organization and/or start your own local group.

Physician-assisted dying

If there was more widespread acceptance of cryonics the harmful delay between pronouncement of legal death and the start of cryonics procedures would not exist. After a determination of terminal illness, preparations would be made to ensure a smooth transition between the terminal phase and long term care at cryogenic temperatures.

Some states have enacted legislation that allows a terminally ill patient to request the means to terminate their life.  Assisted suicide is currently legal in the following three states: Oregon, Washington, and Montana. Physician-assisted dying does not remove the current obstacle that cryonics procedures can only be started after legal pronouncement of death but it can bring the timing of death (and thus of standby) under the patient’s control. Utilizing such laws can also greatly reduce the agonal phase of dying and its associated risk of damage to the brain.

The legal requirements for utilizing physician-assisted suicide can vary among states but, as a general rule, require that a patient has been diagnosed with a terminal illness with no more than six months to live, that the patient is of sound mind, and that the request is made in written form and witnessed. The State of Oregon has a residency requirement to discourage physician-assisted dying tourism.

Since cryonics procedures are performed after legal death, there is no reason why cryonics patients are exempt from utilizing these laws. Despite rumors to the contrary, there is no evidence that utilization of these laws require mandatory autopsy. After all, the cause of death in physician-assisted dying is clear; self- administration of the lethal drug. To avoid any possible accusations that cryonics organizations encourage the use of such laws, it is recommended that no person associated with the cryonics organization should be a witness, let alone be the physician that prescribes the lethal drugs.

Sudden death and autopsy

One of the worst things that can happen to a cryonics member is sudden death. Especially when the patient is young with no prior heart conditions, an autopsy is almost guaranteed. There is little one can do to avoid sudden death aside from choosing a lifestyle that reduces cardiovascular pathologies. The only preparation for dealing with sudden death is to become a religious objector to autopsy. Some states (including California, Maryland, New Jersey, New York and Ohio) have executed laws to restrict the power of the state to demand an autopsy. Although exceptions can still be made in cases of homicide or public health there is little to lose in using such provisions. The websites of Alcor and CI have links to the relevant forms to execute. The Venturists are offering a card for their members stating that they object to autopsy. This card can be requested from Michael Perry (mike@alcor.org) at Alcor. An example of such a card is provided below.

Sudden cardiac death is not the only reason for ordering an autopsy. An autopsy is typically ordered if there are criminal suspicions (homicide) or suicide. There is also a greater risk of autopsy when a patient dies in absence of other people. Since many old cryonicists are single and spent a lot of time alone they are also at an increased risk for autopsy. This is another good argument to remain involved with local cryonics groups and in frequent contact with other cryonicists.

If autopsy cannot be avoided it is important that the cryonics organization is notified promptly. Cryonics organizations can make another attempt to persuade the authorities to abstain from an autopsy or to request a non-invasive autopsy that exempts and protects the brain. The cryonics organization can also issue instructions for how the patient should be maintained prior, during and after autopsy. It might be worthwhile to generate a template of general autopsy instructions for cryonics patients. Such a document may not be binding but it could be useful in limiting the amount of ischemia and injury.

The dying phase and Advance Directives

Most cryonics members have a basic understanding of the importance of time and temperature to protect a cryonics patient after legal pronouncement of death. Fewer people recognize the effect of the dying process itself on the outcome of a cryonics case. In best case scenarios (physician-assisted dying, withdrawal of ventilation) the dying phase is relatively rapid while in worst case scenarios extensive ischemic injury to the brain is possible. Little work has been done to outline recommendations for the terminally ill cryonics patient. One of the main objectives of this article is to recognize that cryonics members could benefit from a general template that can be used in their Advance Directives and to guide surrogate decision makers.

At this point it is useful to briefly describe how the dying phase itself can affect the outcome of cryonics procedures (for a more detailed treatment see the appendix at the end of this article). A useful distinction is that between terminal illness and the agonal period. A patient is classified as terminal when medical professionals establish that the patient cannot be treated with contemporary medical technologies. During this period the patient is usually still of sound mind and able to breathe and take fluids on his/her own. Unless the patient has suffered an insult to the brain or a brain tumor, there is no risk for ischemic injury to the brain yet. At some point, however, the body’s defense mechanisms will be overwhelmed by the patient’s disease and the patient enters the agonal phase. The agonal phase, or active dying phase, can be characterized as a form of general exhaustion. The body is still fighting but with decreasing success and efficiency. One of the biggest concerns for cryonics patients is the development of (focal) brain ischemia while the (core) body is still mounting its defense.

It would be impossible to design an Advance Directives template that is optimal for all cryonics patients, but there are a number of general guidelines that can inform such a document:

* All health care decisions should be guided by the objective of preserving the identity of the patient throughout the terminal and dying phase.

* Measures to prolong dying should only be initiated or accepted if they result in less ischemic injury to the brain.

* Life-sustaining measures should be withheld in case of traumatic or ischemic insults to the brain.

To ensure that sensible decisions are made in situations that are not covered by these Advance Directives, a Health Care Proxy can be executed that designates a person to make those decisions. It is understandable to give such power to the person closest to you but in the case of cryonics it is recommended that this responsibility should be given to a person with a strong commitment to your desires and a detailed understanding of the medical needs of cryonics patients.

Pre-medication of cryonics patients

If a critically ill cryonics member is at risk of ischemic brain injury during the dying phase it stands to reason that some palliative treatment options are better than others. One possibility for cryonics patients is to specify such options in one’s Advance Directives. Another scenario in which pre-medication is possible is where the medical surrogate is strongly supportive of such measures. It should be noted that such a decision rests solely with the member or his/her medical representative. Cryonics organizations should not be involved in the pre-mortem treatment of the patient.

There are two important questions about pre-medication of cryonics patients:

1. Is it safe?

2. Is it beneficial?

The answer to the first question has a lot to do with the status of the pharmaceutical agents in question. For example, a supplement like melatonin is less controversial than a prescription drug like heparin. The most important thing to keep in mind is that drugs that may be beneficial after legal pronouncement of death could have adverse effects in critically ill patients. Good examples are drugs that have effects on blood rheology and clotting. One would rather forego the hypothetical benefit of a drug if there is a non-trivial change of triggering major controversies about drugs taken during the dying phase. This leaves only certain supplements as relatively safe options for pre-medication of cryonics patients.

The answer to the second question is not clear. The rationale behind pre-medication is that it can protect the brain during agonal shock and its associated ischemic events. Evidence for this belief is usually found in the peer reviewed literature on neuroprotection in ischemia. However, there is a clear difference between the administration of neuroprotective agents during the dying phase and the administration of neuroprotective agents prior to artificially-induced acute ischemia. One perspective is that such agents are beneficial but only delay the ischemic phase of the dying period. In this case supplements have little neuroprotective effect. An alternative perspective is one where such supplements do not alter the agonal course as such but provide more robust protection after circulatory arrest. Obviously, this matter is not of concern to conventional medicine so there is little evidence to make rational decisions. In light of the previous discussion, the current (tentative) verdict should be that a case can be made for pre-administration of neuroprotective agents but that these agents should be confined to “safe” supplements like melatonin, Vitamin E and curcumin. Whether such a regime would be beneficial needs to be decided on a case by case basis and is, therefore, more in the domain of the Health Care Proxy than Advance Directives.

Do Not Resuscitate Orders

Do Not Resuscitate (DNR) orders present one of the most challenging issues for cryonics optimization. On the one hand, we would like to benefit from any attempt to resuscitate us in case of sudden cardiac arrest (or any other acute events that can lead to death). On the other hand, we would not like to be subject to endless rounds of futile resuscitation attempts that can damage the brain.

One would be inclined to think that resuscitation attempts should be made in case of sudden insults or during surgery but that no resuscitation attempts should be made during terminal illness. In reality things are not that simple. For example, resuscitation may be possible after 8 minutes of cardiac arrest but the patient can suffer severe brain damage as a consequence. Such a scenario can be minimized by executing a DNR at the cost of foregoing any resuscitation attempts at all. Would this outweigh the benefits of successful resuscitation attempts? It is hard to see how an objective answer to this question can be given without taking a specific person’s views on risk and treatment into account. One way to mitigate this dilemma is to make a distinction in your Advance Directives between pre-arrest emergencies (for example, resuscitation should be permitted in the case of labored breathing but presence of heart beat) and full arrest. An in-hospital situation where resuscitation of a critically ill patient would be helpful would be where it would allow a cryonics standby team to deploy at the bedside of the patient. As can be seen from these examples, good resuscitation instructions for cryonics patients require a lot of attention to context. Because confusion could arise whether Advance Directives would include pre-hospital emergency procedures it is recommended to execute an explicit document if you want these cases to be covered – such a document could be complemented by wearing a bracelet.

Creating a general template

This article has identified a number of important medico-legal issues that need to be addressed by cryonicists to optimize their cryopreservation. It has become clear that in the case of many topics we would all benefit from uniform and effective language. The next step is to translate the concerns discussed in this document in clear legal language so that templates can be offered to all members of cryonics organizations to draft their own Living Will and Advance Directives. One potential problem of such a general template is that it may not conform to state regulations and needs additional tweaking to make it valid in the state where the person lives.


Appendix :  Neurological damage during the dying phase

Securing viability of the brain by contemporary criteria is the most important objective of cryonics standby and stabilization. Recognition of how pathological events in the central nervous system can defeat this objective is of great importance. As a general rule, the risk for increased brain damage is higher during slow dying. For example, when the ventilator is removed from the patient who is not able to breathe on his own the time between this action and circulatory arrest can be short. Conversely, when a patient is going through a prolonged terminal and agonal phase (regional) injury to the brain can occur while the body itself is still fighting for its survival.

The human brain has little storage of excess energy. As a result, hypoxia causes the brain to deplete its oxygen reserves within 30 seconds. The energy depletion that follows cerebral hypoxia during the dying phase has a number of distinct effects: 1) excitation or depression of certain processes in the brain, 2) alteration in the maintenance of structural integrity of tissues and cells, and 3) alteration of neuromediator synthesis and release. The depletion of oxygen leads to a switch from aerobic to anaerobic energy production. As a consequence, there is an increase in the metabolic end-products of glycolysis such as lactic acid which decreases pH in the brain. After 5 minutes no useful energy sources remain in the brain, which can explain why the limit for conventional resuscitation without neurological deficits is put at 5 minutes as well. Because the dying phase leads to progressively worse hypotension and hypoxia the metabolic state of the brain after the agonal phase is worse than if there would have been sudden cardiac arrest.

Light microscopic changes have been observed in brain cells after 5 minutes of ischemia. Prolonged hypotension, as can occur in the agonal patient, can lead to the appearance of “ghost cells” and disappearance of nerve cells. Such observations provide evidence that structural changes, including cell death, can occur prior to clinical death. Another manifestation of hypoxia (or hypotension) is the progressive development of cerebral edema. The resulting narrowing of vessels and decrease of intercellular space can, in turn, aggravate energy delivery to tissues. Of particular importance for cryonics stabilization procedures is the development of no-reflow which can prevent complete restoration of perfusion to parts of the brain during cardiopulmonary support. There is no consensus as to whether no-reflow can occur as a result of prolonged hypotension (as opposed to complete cessation of blood flow), but an extended dying phase can set the stage for cerebral perfusion impairment after circulatory arrest.

The central nervous system does not shut down at once. Throughout the terminal and agonal phase alternations in the brain progress from minor changes in awareness and perception to deep coma. As a general rule, more recent and complex functions of the brain disappear earlier than the most basic functions of the brain. The uneven brain response to hypoxia may reflect different energy requirements, biochemical and structural differences, and/or the activation of protective mechanisms to preserve the “core” functions of the brain. The CA1 region of the hippocampus has been demonstrated to be uniquely vulnerable to ischemia. This presents a problem for contemporary cryonics since the objective of human cryopreservation is to preserve identity-relevant information in the brain.

This article is a slightly revised version of a paper that was submitted for the 4th Asset Preservation Meeting near Gloucester, Massachusetts.