Cryonics, March 2013

By Max More

• Why do Alcor members have to pay membership dues?
• What are they used for?
• Why do I also have to pay CMS (Comprehensive Member Standby) fees?
• Why can’t we run the organization using income from doing cryopreservations and abolish dues?
• Can’t we just cut our costs?
• How will dues change in the future?

These are questions I hear frequently. Our current level of membership dues is frequently cited as a reason for members — especially those with reduced incomes — to cancel their memberships. (Many of these indicate that it’s not increases in dues that are the main problem; it’s the loss of a job or drop in income. Most of these individuals tell us they intend to return once their financial situation improves.) Alcor’s growth rate has declined over many years, but has slowed to a distressingly low rate in the last few years. It’s entirely plausible that part of this is due to the cost of membership dues.

When I took over as Alcor’s president at the start of 2011, I knew I would face a difficult situation. Just one year earlier, dues were increased from $398 to $478. (Including annual CMS fees of $120 this resulted in an increase from $518 to $598 per year.) That was the first dues increase in eight years. Just one year later, on January 1, 2011 (my first day as president) dues were raised again from $478 to $620 — an increase of 30%. (Including CMS fees — which increased 50% from $120 to $180, this resulted in an increase from $658 to $800 per year.)

The yearly cost of membership from 2002 to 2012 rose quite a bit, especially when you include CMS fees. No CMS fund existed in 2002. That meant that members did not get a standby unless they paid for it at the time they needed it. The universal CMS fee has enabled Alcor to provide everyone with a standby, but it has added to the total yearly cost of membership. The recent large jumps in dues may leave members with the impression that dues have risen more rapidly than is actually the case on average. To put the longer-term increases in context, excluding CMS fees, here are the numbers:

From 1986 to 2013, membership dues rose from $200 to $620, which is 4.28% per year. (This is higher than general inflation, but only marginally.)

Looking at the last 18 years, from 1995 to 2013, dues went from $398 to $620, which is 3.07% per year. (Medical inflation exceeded 10% annually in the 1990s, and 6% over the last few years.)

Why so high and why the increases?

Clearly, dues have risen significantly. But let’s put the rise in the context of overall inflation. When dues were increased by 10% back in 2002, that increase lagged the CPI increase of 16% over the same period. In other words, dues were not raised enough to keep up with the general rise in prices. When that lag is allowed to build up over years, the adjustment becomes more painful. Almost a decade went by before dues were again adjusted. Even as recently as 2010, Alcor’s dues were only $30 a year greater than they were in 1992 after adjusting for inflation. Only at the start of 2011 did the rise in dues finally move significantly above the rate of inflation.

Apart from catching up with inflation, the one-two punch of 2010 and 2011 were necessary to enable Alcor to tackle its structural deficit. (By “structural deficit” I mean a deficit when irregular and unpredictable revenue from bequests, donations, grants, and cases is excluded. Alcor has shown an apparent budget surplus over the last two years, but still has a structural deficit.) Since a substantial grant was expiring after three years, a deficit of $400,000 was projected if no action were taken.

Over years and decades, some of Alcor’s expenses rose substantially. Employee expenses account for a large part of overall expenses. Those expenses rose significantly over the years as Alcor transitioned away from a volunteer-based to a professional organization (starting very modestly in the 1980s) and found itself paying more market-based salaries. I do not expect this increase to continue. On the contrary, if we can grow our organization, I believe that we are at a point where economies of scale can be reaped: we could double or triple our membership without coming even close to doubling or tripling staff costs. But the painful dues increases of recent years have reflected the reality of catching up with inflation and with realistic employee costs rather than unsustainable volunteerism.

Quite a few members do not pay the full $800 per year. They pay significantly less if they are family members, students, or members of 20 years or more. This will not be much comfort if you pay the full amount. You may be grumbling at the cost even if you understand the need to catch up with inflation and to tackle budget deficits. Even so, consider that this amount is a less-daunting $67 per month. On a still shorter-term basis, your last, best chance to beat death is setting you back $2.19 per day in dues. That’s a little more than a tall cup of coffee at Starbucks (and quite a bit less than a short latte).

This is significant for some members; for others, it may be more the rapid recent increases rather than the actual cost which are problematic. Considered as a daily or weekly amount, the cost of membership may seem quite modest. But the success of cryonics for any particular individual is highly uncertain, while the current cost is real and obvious. Even if — for most members and many potential members — the cost is quite manageable when considered objectively, willingness to pay is based on perceptions of costs and benefits, not necessarily on objective facts.

At current levels, it’s seems clear to me that dues cannot increase (beyond pacing inflation) without reducing membership retention and growth. So, my remarks about the (objective) modest-for-many costs of cryonics should not be taken to suggest that I am in the least dismissing concerns about rising costs, or that I am not doing all in my power to address those concerns. I have no doubt that the current level of dues is resulting in lost members and is making it harder to attract new ones. Growth is important to deepen our resources — so we can defend ourselves against attacks, do more research, and ensure the continued existence and resilience of the organization.

Why not pay for operating expenses from Cryopreservation Fund income?

Doesn’t it make sense to pay operations out of the income from the service of providing a cryopreservation and longterm care? After all, Alcor isn’t like a club where you pay monthly or yearly dues in exchange for specific services.

Membership dues have never been sufficient to cover all of Alcor’s recurring costs, so we have relied on other sources of income, including donations and bequests. But let’s restrict ourselves solely to considering what it would take to replace membership dues. Membership dues will bring in an estimated $453,000 in 2012 (that’s after allowing for bad debt). So that’s the amount that would have to be generated from case income.

Given Alcor’s existing membership base and the distribution of ages and life expectancies, we expect about eight cryopreservation cases per year. The actual number varies wildly: Not long ago, we had 12; in 2012 we had only three. Suppose all cases were not only fully funded but each cryopreservation fund averaged $40,000 above current minimums. If we continue the practice of distributing half of these funds to the PCT and half to operations, those eight cases would generate 8 x $20,000 = $160,000 for operations. We would need to have almost 23 cases per year, funded $40,000 above minimums, to replace membership dues.

This is very much an approximation. On one hand, we might reduce the estimated number of annual cases needed to eliminate dues because most cases funded exactly at the minimum should produce a modest gain for operations. However, this varies by case and is not always true. On the other hand, the 50/50 split between PCT and operations is only a default. We use that rule when a member does not specify the distribution of funds above the minimum. Most of those who do specify a distribution give it all to the PCT, or some to research, with very little to going to operations. This would have to change in order for over-minimum funding to have a major impact on dues. The actual number of cases per year required to reach the “dues-replacement level” might therefore be 23, or 40, or any other number, depending on assumptions about over-minimum funding and distribution of that funding.

By the time our membership has grown enough to reach the dues-replacement level, expenses would probably have risen (although I expect costs to rise considerably less than proportional to membership size from this point on). So the dues-replacement level would then be higher than on the assumption of fixed operating costs.

The problem should be obvious. Even if all members provided cryopreservation funds $40,000 over minimums, we would need at least three times as many cases as we can reasonably expect today in order to generate sufficient revenue to replace membership dues. Compounding the challenge, most Alcor members today are funded at levels below current minimums. These cases are likely to drain operating funds.

But this is not an all-or-nothing matter. I would like to see us move gradually in the direction of funding operations more from cryopreservations and less from membership dues. This will take time and growth and major improvements in funding of cryopreservations. We could shift funding much faster in that direction if we received major bequests, especially if some went to the Endowment Fund and some to the Operational Reserve Fund. The uncertainty of bequests and of operational income from cases is why these are excluded from calculations of the structural deficit. As membership grows, we should be able to gradually make allowance for these more irregular forms of income, recognizing their contribution to the structural budget and thereby having a downward effect on membership dues.

How will dues change in the future?

Let us separate out the likely trajectory of (a) basic membership dues from (b) membership dues as they may be for any particular individual if we adopt an Underfunding Plan in which members with below-minimum cryopreservation funds pay additional dues to partly compensate. (That would only happen if they did not raise their funding to current minimums or, in the case of whole body members, refused to be switched to neuro member status, and who do not qualify for the Hardship Fund.) I will consider here only the plausible direction of membership dues for members funded at current minimums or higher.

All other factors being equal, dues will depend mainly on costs and growth rates. As I mentioned earlier, I believe we have reached a point where further membership growth will allow us to reap economies of scale: We can increase membership with a less than proportional increase in operating expenses. Posited economies of scale are not mere wishful thinking: Consider that, say we grow our membership by 100%: while we might need some additional help in some areas, we would not need to hire a second president, or a second finance director, and so on. Only in 2012 did we introduce Associate Membership, an option that is essentially costless and yet which could generate significant income if we can grow this category into the hundreds or higher. At the same time, future increases in employee costs should closely track overall increases in compensation throughout the economy (tracking a combination of inflation and productivity gains), with little or no need for catch-up increases.

In addition, we have been and will continue to take measures to control and reduce costs where possible. For instance, I eliminated one full time position; it may be possible to reduce employee costs further; we are renegotiating contracts and licensing arrangements; requiring that all new ongoing expenses be compensated by cuts in other areas (until structural budget balance is achieved); and have insulated the building to save several thousand dollars annually. We are also benefiting from Life Extension’s generous support in covering the production and distribution of Cryonics magazine.

These core factors strongly suggest that if we can grow membership, we should be able to hold down membership dues. If growth is slow, while inflation continues to average around 3% annually, we may only be able to prevent further rises. If growth is stronger, reduction in dues becomes feasible.

Currently, the 2% draw from the Endowment Fund adds about $70,000 to operating funds. If we can grow the Endowment Fund, that 2% draw will grow. Suppose we were fortunate enough to receive a $10 million infusion. That would generate an additional $200,000 annually. That would be equivalent to 44% of the income expected from membership dues for 2012. Even after eliminating the structural deficit, that would allow a significant reduction in dues. We cannot know the amounts involved, but we should work toward building the Endowment Fund over time. This will help keep a lid on — and perhaps reduce — membership dues.

Here’s another possibility: Suppose our wealthier members recognize the benefits of improving retention and growth in number of members, and contribute to a fund specifically intended to subsidize dues over a period of time (perhaps ten years). The idea would be to use the fund provided to cut dues so as to accelerate membership growth, to reach a point where the additional members would more than replace that fund income (and allow us to reap economies of scale).

We have already noted another factor that could allow us to progressively reduce membership dues — and possibly one day eliminate them altogether: An increase in bequests and over-minimum funding of cryopreservations, some part of which is directed to operations. We are currently thinking about one step in this direction: The possibility of reducing or waiving CMS fees for sufficiently well-funded members. This may turn out not to be feasible, but it’s a possibility we are pondering.

To those members who have been with us for many years, let me point out that we have recently introduced a new discount ($186 reduction per year) for individuals who have been members for 20 years or longer. This is intended to reward members who support Alcor over the long haul, and to show that they will not face ever-rising dues. I will be proposing further discounts for members of 25 years’ and 30 years’ standing.

Finally, I understand that my grounded optimism about future dues may not greatly comfort those of you who are struggling today. You may have lost your job, or retired, and been forced to take a lower-paying job in this difficult economy. Whatever you do, if you are struggling, talk to us. We work with members as best we can. If you’ve fallen far behind in paying dues and you never respond to our communications, eventually your membership will be cancelled. Talk to us, show willingness to work with us, and we can figure something out.

My thanks to Bonnie Magee for suggestions that improved this article.

Cryonics, March 2013

By Aschwin de Wolf

In a previous column called “Iatrogenesis and Cryonics” I observed that cryonics is uniquely vulnerable to iatrogenic injury because the objectives of individual cryonics procedures (such as stabilization) are not clearly defined and due to the lack of obvious feedback that a low temperature stabilization procedure entails. This does not mean that cryonics advocates have not thought about how to look at the overall quality of a cryonics case. On the most general level we can evaluate a cryonics case by looking at the degree to which the cryonics stabilization procedure itself adds additional injury to the patient. This is important because critics of cryonics are usually more skeptical about the effects of stabilizing the patient at cryogenic temperatures than about the idea that a person who is considered terminally ill today may not be considered terminally ill in the future. The idea that the cryonics procedure itself does not add additional injury to the patient also ties in with the idea that one of the most important mandates of medicine is to do no harm.

What can a credible cryonics organization do to move its procedures in the direction of reversibility? At the most general level it can reflect this by formally recognizing the goal of developing human cryopreservation technologies that are injury-free. In terms of a research objective, this means that it should aim for human suspended animation. The idea of reversible human cryopreservation is straightforward and easy to communicate. In fact, most laypeople who first hear about cryonics intuitively grasp this point. It also provides a useful benchmark to assess the degree of technological progress at a cryonics organization and evaluate the performance of a cryonics organization in cryopreserving humans.

But how can the concept of reversibility be applied to a cryonics organization that has not yet perfected reversible human cryopreservation? In this case one can still ask how far we can push the goal of reversibility. This raises another challenge. How can we know to what point our procedures are still reversible if we do not actually reverse them? For starters, we can look at the limits of conventional medicine (hypothermic circulatory arrest) and ensure that our procedures conform to the physiological requirements of these procedures. Another (complementary) approach is to define reversibility as maintaining viability of the brain and collect data that will provide us with an answer regarding how well we have achieved this objective.

As I write this, our understanding is that, under ideal circumstances, we can keep the brain viable up to at least the early stages of cryoprotective perfusion (which is conducted around 0° Celsius). It would be desirable to have a better empirical understanding of this, and one approach would be to take a very small, microliter brain sample of a patient (an established harmless medical procedure) and subject it to a variety of viability assays (such as the K+/Na+ ratio). A fruitful research objective would be to achieve loading and unloading of a vitrifiable concentration of cryoprotectant in the brain and recover organized electrical activity (EEG) in a suitable animal model and then modify this protocol for human cases. If we achieve this, viability of the brain may be retained during the descent to cryogenic temperatures.

Currently the “descent to cryogenic temperatures” is not a completely innocuous step because thermal stressinduced fracturing can still produce mechanical damage. To eliminate this form of damage and transform the challenge of reversible human cryopreservation into a biochemical problem, intermediate temperature storage appears to be a requirement.

Cryonics, February 2013

By Laurence Mueller, Cassandra Rauser, and Michael Rose, New York: Oxford University Press, 2011.

Book Review by R. Michael Perry

The book here reviewed is a technical study on the effects of aging, mainly using fruit flies as a model, since these creatures are short-lived so that research involving many generations is feasible. The findings appear to have relevance to other animal species, including humans.

It is customary to think of aging as a process of progressive deterioration, akin to rust, that finally ends the life of the organism. The growing disability and decline in health, it is said, is reflected in an ever-increasing mortality or chance of dying in a given time interval. Not so, say the authors. Instead, though mortality does increase throughout much of later life in organisms ranging from insects to humans, finally but definitely it plateaus or levels off to more or less a constant value—aging stops. After this death still occurs, but at a nearly fixed rate, and the organism in this “late life” period does not experience any additional ongoing deterioration. Aging is not really a “process,” say the authors, but is best understood as a result of decreasing selection pressure as the organism repeatedly reproduces and the need for its continued survival correspondingly diminishes.

The absence of selection pressure, the authors say, means that features of the organism that are both beneficial and not subject to deterioration with time, that is to say are age-independent, persist unchallenged through time, allowing the late life period of little or no further deterioration to emerge. This theory was first developed by William D. Hamilton in the 1960s, and is invoked throughout to explain the extensive experimental findings based mainly on the life histories of fruit flies.

The work reported with fruit flies (Drosophila melanogaster) was long and extensive, covering 18 years and 465 generations, supplemented by a lesser amount of work with a related, also shortlived insect, the medfly (Cerititis capitata). The fruit flies averaged about 14 days per generation and lived up to a little past 100 days. Roughly, the length of generations and maximum life-span of the fruit flies in days equaled these data for humans in years, which thus are scaled several hundred times longer.

As for the results, it is consistently shown that the mortality of fruit flies, measured in terms of a probability density function giving the chance of dying in a short time interval, does not indefinitely increase. Instead it levels off or plateaus in later life, approaching a roughly constant value in which about 15-30% of the flies die per day, the variations depending on such factors as whether the flies have been specially bred for longevity. Though this is a substantial attrition rate, it is significant that it does not change much from this point on and particularly does not approach 100%, contrary to the thinking of earlier times. Instead, following the period of “aging” in which mortality rates rise, there is a period of indefinite if still finite length that the authors call “late life” when the organism does not age any further, though the aging that has already occurred is not reversed. The study was extended to cover fecundity, measured by the number of eggs produced per female fly per day. Here too it was found that rates plateaued at nonzero values, in this case about 1-5 eggs/day, starting around age 60 days, versus about 50 eggs/ day at peak performing ages of 20-30 days. The plateauing, both of mortality and fecundity, was highly insensitive to such effects as whether the particular strains of flies were shorter-lived or longer-lived, or had started out longer-lived and been selectively bred to be shorter-lived.

The authors note that other explanations for the onset of late life than the one they offer (Hamilton’s theory of diminishing selection pressure with time) have been proposed, and detail their considerable efforts to rule out these other explanations. Thus for example, there is a heterogeneity theory: a population of individuals contains some that are more likely to live long than others due to genetic variations. As the population ages, the shorter-lived variants die off leaving the longer-lived who then drive the mortality to lower levels than would otherwise occur. This hypothesis is carefully tested, however, and the authors find that selection pressure works against heterogeneity by pruning the less fit, enforcing a uniformity that defeats this explanation of late-life plateauing.

The study was done with flies, though we are naturally more interested in ourselves, and particularly, whether humans like flies have a late-life period of indefinite duration in which aging has ceased. Humans, though, are much longer lived, and even a short-lived mammalian cousin such as the mouse would present formidable obstacles for laboratory research, requiring about a century to carry out a study to the same limit (465 generations, 12 weeks each in this case) as was done with the fruit flies. The authors caution against using human demographic data with the same confidence as data from the carefully controlled experiments they and others have undertaken with insects. The decline in mortality with age nevertheless occurs in other species too, the authors note, so that with humans in particular mortality has been found, tentatively, to reach a constant somewhere in the age range of 90-105, with roughly 50% of individuals (both genders) dying per year from then on. The authors conclude that late life in humans is broadly in line with the Hamiltonian theory, though the details of what is happening physiologically are complex and still not well understood.

But the authors pose the question: why does late life in humans begin so late? Moreover, could it be induced to happen earlier, when one’s health is much better and mortality much smaller? The hypothesis is considered that the transition from aging to late life occurs so late because of an agricultural diet, to which humans are still imperfectly adapted after some 400 generations or less. Here there are arguments and counterarguments, and the authors caution that more research is needed to test this and some alternative explanations for the lateness of late life. Still, the authors speculate that aging might be made to stop earlier by adopting a huntergatherer diet like that of our preagricultural, paleo ancestors. In any case, proclaim the authors, “gerontology based on cumulative damage or programmed aging is defunct.”

One consequence is that attention must shift, in the fight against aging, from the idea of stopping a small number of forms of cumulative damage, as Dr. Aubrey de Grey has proposed, to recognition of the need to induce late life earlier. The failure to take this latter approach, say the authors, will mean that far too many forms of damage will have to be addressed on an individual basis for any practical antiaging program. As an alternative, the authors propose experimental evolutionary studies in which aging in model species is made to stop earlier and earlier, with corresponding adjustments in the rate of aging, and close study to determine the physiological and biochemical reasons why the changes occur. Such work would step beyond the authors’ own, reported in the book, in which the organisms were treated largely as black boxes in monitoring survival and fecundity. The extra effort, they say, should provide superior insight into halting aging in humans.

One thing stressed in the book is that the hypothesis that aging stops was recognized—and resisted—long before it was widely accepted. Indeed, the present volume is largely an effort to establish this simple hypothesis beyond a reasonable doubt. The large amounts of evidence, both experimental and theoretical (using simulations of fly evolution and related calculations) and the thoroughness with which it is treated will be of interest to the researcher, while by the same token this is not a book for the general public. Such a book in turn might include a chapter summarizing the work covered in the present volume, then go on to cover other topics relating to the aging puzzle and its possible resolution, some of which are yet to be researched. I also think the work of Dr. de Grey, which is mildly criticized near the end, may actually have synergistic value, serving as a useful complement to the antiaging approach advocated here and others that might be attempted.

In any case, the book makes a very persuasive case that aging stops in fruit flies and medflies. It may also stop in humans, but if so it is at such an advanced age, with so high a final mortality, as to be of little benefit. Could human aging be stopped at an earlier age where the mortality would be much lower? And does abandoning the agricultural diet of the past 10,000 years have a significant chance of bringing this about, as the authors very tentatively suggest? To me the jury is still out—more evidence is needed—though admittedly I am skeptical. Our paleo ancestors generally did not live as long as we do. When causes of death such as infant mortality, childhood diseases, malnutrition, predators and adult diseases are taken into account, I still don’t see strong evidence that their aging stopped much earlier than ours. An earlier halt to aging will surely take more than a simple change in diet, one would think. As usual, further investigation is called for.

Cryonics, February 2013

By Chana de Wolf

This is the first entry in a new series of short articles about neuroscience and its implications for the field of human cryopreservation and life extension. In this article I discuss the relationship of the brain to consciousness and knowledge acquisition before venturing into more specific and practical topics

What is consciousness? Most of us understand the word in context, but when asked to define it we are suddenly at a loss for words or at best we offer a description that seems wholly inadequate. Scientists, philosophers, and religious scholars have debated the source, meaning, and nature of consciousness for all of recorded history. But with the rise of neuroscience over the past few decades, it now seems as though explaining the nature and mechanisms of conscious experience in neurobiological terms may be an attainable goal.

The recent work on consciousness by neuroscientists has left certain philosophers more frustrated than ever before, including the likes of Thomas Nagel and David Chalmers. They suspect that consciousness may be quite different and separate from the brain circuitry proposed to underlie it.

Consciousness has appeared to be a strange and undefinable phenomenon for a very long time. Daniel Dennett captured the feeling very nicely in the 1970s:

“Consciousness appears to be the last bastion of occult properties, epiphenomena, immeasurable subjective states — in short, the one area of mind best left to the philosophers. Let them make fools of themselves trying to corral the quicksilver of “phenomenology” into a respectable theory.”(1)

Consciousness no longer appears this strange to many researchers, but the philosophers just mentioned continue to hold that it may not be reduced to brain processes active in cognition. A common philosophical complaint is that any neurobiological theory of consciousness will always leave something out. What it will always leave out is the feeling itself — the feeling of what it is like to be aware, to see green, to smell flowers, and so on (Nagel 1974; Chalmers, 1996). These are so-called qualia — the experiences themselves — and these are what are important about consciousness. The philosopher making this argument may go on to conclude that no science can ever really explain qualia because it cannot demonstrate what it is like to see green if you have never seen green. Ultimately, they argue, consciousness is beyond the reach of scientific understanding.

By contrast, neuroscientists take for granted that consciousness will be domesticated along with the rest of cognition. Indeed, this work tends to assume that neuroscience will not only identify correlates of consciousness, but will eventually tell us what consciousness is. By and large, these neuroscientific efforts have been directed toward cortical regions of the brain, cortical pathways, and cortical activity. This is due, in part, to the prevalence of clinical studies of human patients with region-specific cortical lesions that are correlated with deficits in specific kinds of experiences. This tendency to focus on the cortex may also reflect the common knowledge that humans possess the highest level of consciousness of all animals and have proportionally more cortex than our closest relatives (and — so the supposition goes — therein lies the difference in levels of consciousness).

Another theory of consciousness, offered by Dr. Gerald M. Edelman, aims to resolve this “divorce” between science and the humanities over theories of consciousness. The premise of Edelman’s theory is that the field of neuroscience has already provided enough information about how the brain works to support a scientifically plausible understanding of consciousness. His theory attempts to reconcile the two positions described earlier by examining how consciousness arose in the course of evolution.

In his book on the topic, Second Nature: Brain Science and Human Knowledge, Edelman says:

“An examination of the biological bases of consciousness reveals it to be based in a selectional system. This provides the grounds for understanding the complexity, the irreversibility, and the historical contingency of our phenomenal experience. These properties, which affect how we know, rule out an all-inclusive reduction to scientific description of certain products of our mental life such as art and ethics. But this does not mean that we have to invoke strange physical states, dualism, or panpsychism to explain the origin of conscious qualia. All of our mental life, reducible and irreducible, is based on the structure and dynamics of our brain.“

In essence, Edelman has attempted to construct a comprehensive theory of consciousness that is consistent with the latest available neuroanatomical, neurophysiological, and behavioral data. Calling his idea Neural Darwinism, Edelman explains that the brain is a selection system that operates within an individual’s lifetime. Neural Darwinism proposes that, during neurogenesis, an enormous “primary repertoire” of physically connected populations of neurons arises. Subsequently, a “secondary repertoire” of functionally defined neuronal groups emerges as the animal experiences the world. A neural “value system,” developed over the course of evolution and believed to be made up of small populations of neurons within deep subcortical structures, is proposed to assign salience to particular stimuli encountered by the animal in order to select patterns of activity.

For example, when the response to a given stimulus leads to a positive outcome the value system will reinforce the synaptic connections between neurons that happened to be firing at that particular moment. When a stimulus is noxious, the value system will similarly strengthen the connections between neurons that happened to be firing at the time the stimulus was encountered, thus increasing the salience of that stimulus. When a stimulus has no salience, synaptic connections between neurons that fired upon first exposure to that stimulus will become weaker with successive exposures.

Importantly, the mapping of the world to the neural substrate is degenerate; that is, no two neuronal groups or maps are the same, either structurally or functionally. These maps are dynamic, and their borders shift with experience. And finally, since each individual has a unique history, no two individuals will express the same neural mappings of the world.

This brings us to the three tenets of Edelman’s theory:

1. Development of neural circuits leads to enormous microscopic anatomical variation that is the result of a process of continual selection;

2. An additional and overlapping set of selective events occurs when the repertoire of anatomical circuits that are formed receives signals because of an animal’s behavior or experience;

3. “Reentry” is the continual signaling from one brain region (or map) to another and back again across massively parallel fibers (axons) that are known to be omnipresent in higher brains.

Edelman thus believes that consciousness is entailed by reentrant activity among cortical areas and the thalamus and by the cortex interacting with itself and with subcortical structures. He suggests that primary consciousness appeared at a time when the thalmocortical system was greatly enlarged, accompanied by an increase in the number of specific thalamic nuclei and by enlargement of the cerebral cortex — probably after the transitions from reptiles to birds and separately to mammals about a quarter of a billion years ago. Higherorder consciousness (i.e., consciousness of consciousness), on the other hand, is due to reentrant connections between conceptual maps of the brain and those areas of the brain capable of symbolic or semantic reference — and it only fully flowered with hominids when true language appeared. Regarding language and its relationship to higher-order consciousness, Edelman explains:

“We do not inherit a language of thought. Instead, concepts are developed from the brain’s mapping of its own perceptual maps. Ultimately, therefore, concepts are initially about the world. Thought itself is based on brain events resulting from the activity of motor regions, activity that does not get conveyed to produce action. It is a premise of brain-based epistemology that subcortical structures such as the basal ganglia are critical in assuring the sequence of such brain events, yielding a kind of presyntax. So thought can occur in the absence of language….

The view of brain-based epistemology is that, after the evolution of a bipedal posture, of a supralaryngeal space, of presyntax for movement in the basal ganglia, and of an enlarged cerebral cortex, language arose as an invention. The theory rejects the notion of a brainbased, genetically inherited, language acquisition device. Instead, it contends that language acquisition is epigenetic. Its acquisition and its spread across speech communities would obviously favor its possessors over nonlinguistic hominids even though no direct inheritance of a universal grammar is at issue. Of course, hominids using language could then be further favored by natural selection acting on those systems of learning that favor language skills.”

Such a theory is attractive because it does not simply concentrate on conscious perception, but it also includes the role of behavior. We do well to keep in mind that moving, planning, deciding, executing plans, and more generally, keeping the body alive, is the fundamental business of the brain. Cognition and consciousness are what they are, and have the nature they have, because of their role in servicing behavior.

An important element of Edelman’s theory that consciousness is entailed by brain activity is that consciousness is not a “thing” or causal agent that does anything in the brain. He writes that “inasmuch as consciousness is a process entailed by neural activity in the reentrant dynamic core it cannot be itself causal.” This process causes a number of “useful” illusions such as “free will.”

Edelman’s theory of consciousness has further implications for the development of brain-based devices (BBDs), which Edelman believes will be conscious in the future as well. His central idea is that the overall structure and dynamics of a BBD, whether conscious or not, must resemble those of real brains in order to function. Unlike robots executing a defined program, the brains of such devices are built to have neuroanatomical structures and neuronal dynamics modeled on those known to have arisen during animal evolution and development.

Such devices currently exist — such as the “Darwin” device under development by The Neurosciences Institute. Darwin devices are situated in environments that allow them to make movements to sample various signal sequences and consequently develop perceptual categories and build appropriate memory systems in response to their experiences in the real world.

And though Edelman recognizes that it is currently not possible to reflect the degree of complexity of the thalmocortical system interacting with a basal ganglia system, much less to have it develop a true language with syntax as well as semantics, he nevertheless suggests that someday a conscious device could probably be built.

More ambitiously, Edelman also thinks that contemporary neuroscience can contribute to a naturalized epistemology. The term “naturalized epistemology” goes back to the analytical philosopher Willard Quine and refers to a movement away from the “justification” (or foundations) of knowledge and emphasizes the empirical processes of knowledge acquisition. Edelman is largely sympathetic towards Quine’s project, but provides a broader evolutionary framework to epistemology that also permits internal states of mind (consciousness).

1 Daniel C. Dennett, “Toward a Cognitive Theory of Consciousness,” in Brainstorms: Philosophical Essays on Mind and Psychology (Montgomery, VT: Bradford Books, 1978).

Cryonics, January 2013

By Chana de Wolf

In honor of its 40th anniversary, Alcor held its first conference in 5 years on October 19-21, 2012, in Scottsdale, Arizona. The program featured a wide variety of topics for presentation, with themes regarding how to improve the odds of a successful cryopreservation and theories of aging and their implications for stopping or reversing aging (as argued by their primary scientific proponents). Registration to the event opened on Friday and a reception was held where many attendees spent the evening networking and saying hello to old and new friends alike. But the real fun began Saturday morning with the start of the conference.

Greg Fahy, Ph.D.

The Chief Scientific Officer of 21st Century Medicine, Inc. (21CM), Greg Fahy, kicked off the event with an overview of the work being carried out at 21CM in his talk “Progress Toward Reversible Cryopreservation of Complex Systems.” Because cryonics is reliant upon technologies that do not yet exist, it is sometimes likened to religion. “Unlike religion, cryonics must be based on evidence,” Fahy began, emphasizing that reversibility is the key component of successful suspended animation.

Incorporating elements of the ongoing “debate” concerning chemopreservation as an alternative to cryopreservation, Fahy questioned chemopreservation and its underlying dependence on mind uploading, arguing that “a map of a city is not the city.”

A review of progress in cryopreservation included exciting results in electrophysiological studies of cryopreserved brain slices, including the persistence of LTP in adult rabbit hippocampal slices and recent forays into electromagnetic warming as a way to ensure thermal uniformity across samples during rewarming. Fahy also discussed improvements in cold storage solutions and the long-sought ability to reproduce earlier successful results with M22, Alcor’s primary vitrification solution, in the rabbit kidney after 5 long years of complications.

An interesting discussion about shrinking of the brain as a side-effect of cryopreservation highlighted the role of the intact blood brain barrier (BBB) in perfusion of cryoprotectants through the circulatory system to reach the brain. Fahy gave several examples of attempts to open the BBB in order to reduce or eliminate shrinking, including the use of high perfusion pressures, eliminating large polymers such as polyvinylpropinol (PVP) from cryoprotectant solutions, “preloading” of cryoprotectants, and perfusing at higher temperatures – all of which were unsatisfactory. Ultimately, though, the question is whether preventing brain shrinkage improves neural ultrastructure.

Fahy rounded things out with an update on 21CM’s “20 year plan.” Begun in 2010, their work in whole body vitrification has marched forward with the ultimate goal of reversibility by 2030. Precision perfusion control systems have allowed for unprecedented data collection during whole body vitrification experiments. Currently, the company is focusing on studies of cryoprotectant toxicity to make the next advance toward reversible cryoprotection of the most complex system of all, the whole organism.

Chana de Wolf, M.S.

Following Greg Fahy was my own presentation of the work being carried out by Advanced Neural Biosciences, Inc. (ANB). ANB is a neural cryobiology research lab founded in 2008 by Chana and Aschwin de Wolf with an emphasis on optimizing protocols for ischemic patients. In particular, ANB has focused on research involving perfusion and cryopreservation of the ischemic brain. In order to do so, a rat model is used to simulate cryonics procedures under realistic conditions.

The main theme of the presentation was that there is a distinct difference between the ice free brain preservation that can be achieved in the lab and the conditions under which a typical cryonics patient is being cryopreserved. In particular, the variable periods of warm and cold ischemia which precede cryoprotective perfusion produce perfusion impairment (“no-reflow”) and ice formation in the brain after cryogenic cooling. In the case of cold ischemia we found that remote blood substitution with an organ preservation solution can prolong the period of cold ischemia after which ice free preservation is still possible. Some organ preservations are better than others and we observed the best results with MHP-2 (Alcor’s current organ preservation solution). Even after a warm ischemic delay blood substitution still produces better results than not removing the blood prior to cold ischemia, but as the period of warm ischemia increases, so does perfusion impairment and ice formation. I stressed that warm ischemia is not just accelerated cold ischemia, hard to mitigate, and a serious obstacle to good cryopreservation.

We also presented the results of our “field vitrification” research for Alcor. A protocol in which cryoprotective perfusion of the patient is conducted in the field using a simplified protocol followed by shipping on dry ice permits ice free preservation of the brain up to at least 48 hours of dry ice transport. Blood substitution with MHP- 2 and shipping at water ice also permits ice free cryopreservation of the brain for at least 48 hours of cold ischemia but the advantage of a field vitrification protocol is that it eliminates cold ischemic injury to the brain and the severe (whole body) edema that usually is seen during cryoprotective perfusion after long periods of cold ischemia.

In closing, I announced the funding we received from the Life Extension Foundation to conduct whole brain electrophysiology (EEG) studies after cooling and vitrification.

Kim Suozzi

After a mid-morning break, Max More explained that he was giving up one of his speaking slots to Kim Suozzi, whom he introduced as a young woman diagnosed with cancer who wished to be cryopreserved at Alcor. Max announced that Alcor would provide services at reduced cost and that staff would be volunteering time to cryopreserve Kim.

Kim Suozzi, who attended the conference with her boyfriend, then spoke about her terminal diagnosis and efforts to raise money in support of her cryopreservation. Only 23 years old, Kim was a psychology student in her senior year at Truman University planning to do graduate work in neuroscience when she was diagnosed with Grade IV glioblastoma (i.e., brain tumor) after experiencing a multiform seizure in March 2011.

Kim had already become interested in transhumanism, the singularity, and cryonics after reading The Age of Spiritual Machines by Ray Kurzweil, but thought she still had enough time to consider the cryonics option. When diagnosed, she was reticent to ask her parents for financial support, so she posted her request online instead. After getting “unexpectedly good support,” her campaign was picked up by the Society for Venturism, which is currently accepting donations for the Kim Suozzi Charity through their website.

Keegan Macintosh, J.D.

Keegan Macintosh, a young Canadian lawyer and Alcor member since 2011, then presented an in-depth analysis of the Thomas Donaldson legal case entitled “Access to Cryonics: Legal Strategies – Then and Now.” Thomas Donaldson, Ph.D., was an Alcor member who, when diagnosed with Grade II astrocytoma, fought for a declaration that he had a constitutionally-protected right to a “premortem cryopreservation.” Ultimately, his request was denied by California Superior Court.

In his talk, Macintosh critically analyzed how the case was argued and decided at the appeal level. Macintosh emphasized “meaningful access” to cryonics, explaining that Donaldson’s desire for euthanasia via cryopreservation was in order to preserve his brain and personality intact rather than in the state he would be in after his “natural” death. The presented issue was whether Donaldson has a right to premortem cryopreservation, but it was addressed by the courts in terms of assisted suicide.

Because of the very different intentions of these two approaches, Macintosh feels that the issue was considerably confused. He argues that by approaching it as an assisted suicide case, the Court could avoid having to consider the possibility of cryonics ever succeeding. Simply considering relevant state interests, such as preventing suicide and preserving life, should have actually worked for Donaldson’s side rather than the State’s. Other interests, such as protection of innocent third parties and protection of vulnerable persons and preventing abuse, were not relevant at all.

Macintosh believes that we can learn important lessons from analyzing the Donaldson case. In particular, not to avoid the actual issue at hand. After fast-forwarding to the present and discussing some important changes in physician-assisted-suicide legislation in the U.S., Macintosh argued that a case like Donaldson’s may stand a better chance today if these lessons are observed. Interestingly, the successful argument of such a case may be even more probable under the Canadian constitution. In particular, novel arguments could be made under Canada’s Charter of Rights and Freedoms that are not available under the U.S. Constitution.

Panel: Long-Term Financial Planning

Rounding out the morning was a useful panel on long-term financial planning led by Rudi Hoffman, Michael Seidl, and Ralph Merkle.

Rudi Hoffman

Insurance agent and Alcor member Rudi Hoffman introduced the audience to the basics of cryonics funding, including a discussion comparing term vs. permanent life insurance funding options. He highlighted the role life insurance plays in allowing access to cryonics for all and how important it is to emphasize the affordability of cryonics to those considering signing up but who may think that it is available only to the wealthy. That said, Hoffman acknowledged that technological advances and inflation are inevitable and that cryopreservation costs will increase. He urged new and existing members to take these issues into serious consideration when planning cryonics funding and to obtain inflationrobust coverage beyond today’s minimums ($200,000 whole body and $80,000 neuro).

Ralph Merkle, Ph.D.

Ralph Merkle then announced and discussed the Alcor Model Revocable Asset Preservation Trust, recently made available by Alcor to enable cryonics members to preserve their personal assets. In short, Merkle explained, “Your Trust maintains your assets so you ‘wake up’ with your money as well as your life.”

Utilizing an attorney who had written a few wealth preservation trusts for wealthy cryonicists, Alcor drafted a model trust that can be used by most members. Merkle noted that the model trust is used as a starting point to be taken by an individual to his or her attorney to modify to suit their particular situation and purposes. In general, one will need to name a trustee organization (which can be provided by a bank) and three trust advisors (two appointed by the member and one appointed by Alcor). The trust advisors look after the trustee to ensure they do a good job in making financial decisions affecting the trust. Alcor provides continuity after the member’s cryopreservation and appoints successor trust advisors.

Importantly, the Alcor model trust is revocable, meaning that one may take the money out of the trust at any time. Merkle pointed out that the trust also covers other situations separate from financial decisions, such as whether one has been successfully revived. These decisions are handled by Alcor and the trust advisors, not the trustee. Ultimately, Merkle reminds us, there is no precedent for a trust intended to maintain personal assets in perpetuity. “It looks like it should work,” he said, “but we’ll find out.”

Michael Seidl, J.D.

The last presenter in the financial planning panel, Alcor board member Michael Seidl spoke briefly but passionately about ways to ensure that funding is available for your cryopreservation when needed. “Cryonicists are adventurers,” he said, “but we don’t know how long the adventure will take, so we should plan and provision accordingly.” Seidl parsed his recommendations into three commandments:

1. Protect your noggin. Think first about providing for your own cryopreservation. Secure funding that will increase over time.

2. Don’t give people incentive to frustrate your cryopreservation. A large liquid estate can make people crazy. Leaving everything to Alcor could incentivize interference. Provide for these folks so that this incentive is removed.

3. Give people incentive to support your arrangements. For example, provide a financial incentive for a family member to ensure your cryopreservation.

Panel: Medical Monitoring Devices

A post-lunch panel on the current state of medical monitoring devices was hosted by Aaron Drake, Ben Best, and Martine Rothblatt. As in the previous panel, each person was allotted a few moments to speak about the subject.

Aaron Drake

Alcor’s Readiness Coordinator, Aaron Drake, emphasized that a cryonicist’s worst fear is dying alone without being able to notify Alcor. Because time is of the essence in getting a patient from bedside to perfusion, Drake explained that Alcor keeps a cloud-based watch list to track potential cases (e.g., members with known health issues). By doing so, Alcor has increased bedside access to dying members from 33% (in the 1990s) to 86%.

Improving upon 86%, Drake said, will require more sophisticated medical monitoring. Lots of devices exist for measuring all sorts of physiological responses. They may be worn on the body or in the fabric of the clothes. Such devices are not only good for Alcor response, but also for getting to a hospital for immediate care.

Ben Best

Ben Best, former President of Cryonics Institute, followed Drake’s presentation with a discussion of current monitoring devices that might be useful to cryonics. He began by pointing out that a chain is only as strong as its weakest link, and that “the time until pronouncement [of legal death] needs more resources thrown at it.” He is particularly concerned about elderly cryonicists living alone.

While panic-button systems like Life Alert® could be useful, Best thinks it might be better to monitor vital signs (e.g., movement, respiration, heartbeat), which doesn’t require the patient to be alert. Desired features of a device would include rapid detection of loss of vital signs, comfortable wear, ability to send messages, low power consumption, wireless, and minimal false alarms.

Lastly, Best described several ongoing commercial efforts such as Athena GTX, NUVANT Mobile, and MyPulse, as well as some cryonics-specific applications in development, but lamented the fact that working, successful devices still have not materialized.

Martine Rothblatt, Ph.D.

Martine Rothblatt, Director of the Terasem Foundation, then spoke about detection of heartbeat cessation. First she reviewed some statistics describing the way our time is spent and leading to the 2.9% probability (1 in 34) that an Alcor member may suffer delayed response (due to lack of notification of death). The solution to this problem, she said, lies in wireless or Bluetooth external heartbeat detectors or even less sophisticated, wrist-watch style pulse detection devices.

The sometimes low price of these devices lends itself to various economic models that Alcor could implement to generate additional revenue. Rothblatt outlined various models such as: charging for an app and device; giving the app away as a membership benefit; selling or giving away the app and making it modifiable (i.e., not just Alcor-related); and partnering the app and device with one or more PERS (Personal Emergency Response System) companies. PERS is a $125M annual market now, and predicted to be $250M by 2020. If Alcor would take advantage of the 15% annual growth rate of this market, it could generate an additional $1.7M – 27M annually.

Anders Sandberg, Ph.D.

In “Rational Decision Making About Future Technology,” philosopher Anders Sandberg talked with us about “handling the unknowable and undecidable.” He pointed out that even really smart people make really stupid decisions consistently. As a general rule, humans are reasonably good at handling “human” problems, but as we get further out of our comfort zone, we start getting bad at decision-making.

Sandberg described several approaches to decision-making, such as rationality [rational agents maximize their expected utility; but humans don’t have a utility function], irrationality [acting under ignorance and uncertainty isn’t irrational – it’s how we live our lives], and uncertainty [there are some things we can’t or don’t know; we can lack knowledge about parameters or about the rules of a system, or even about what is good]. Unprecedented events are important to consider in the light of uncertainty – “the absence of evidence is not evidence of absence,” Sandberg said. “A true rational person considers the probability of any event as between 0 and 100%. Just because cryonic resuscitation has not occurred does not mean that it won’t.”

Max More, Ph.D.

In an effort to educate old and new members alike, Max More lectured the audience on “How to Be an Exemplary Cryonicist.” He provided a step-by step outline of the myriad things an Alcor member can do to improve their prospects for an optimal preservation, beginning with health maintenance including regular physical checkups and keeping Alcor informed of changes in medical condition. He stressed the importance of keeping your Alcor paperwork updated, wearing your bracelet, and talking to your friends and family about your cryonics arrangements to build understanding and support. He also advocated relocating to the Scottsdale area, avoiding conflicts in financial arrangements, and planning ahead to keep in pace with inflation and maintain adequate funding.

More discussed the things one can do to improve Alcor’s patient care such as giving Alcor access to your medical records and allowing them to perform a CT scan or a sample from the central nervous system to obtain objective feedback about the quality of cryopreservation. Lastly, contributing one’s skills or resources to Alcor as a volunteer and starting or attending a local cryonics group meeting are other great ways to stay involved and to improve your chances of an optimal preservation.

Todd Huffman, M.S.

Following the late-afternoon break, Todd Huffman presented “Advances in Neuroscience: Implications for Cryonics.” Huffman’s focus was on large-scale imaging technologies that can be used to scan and model the brain at various levels of encoding. Particularly interested in neural structure and high throughput light microscopy, Huffman’s company 3Scan has developed the Knife-Edge Scanning Microscope (KESM), capable of imaging tissue while slicing it with a diamond blade to create a stack of images that can be put together to create a 3D image.

Huffman included several beautiful photos of the 3D images captured by the KESM, from an image of the vasculature of a mouse brain to Nissl stains for cell bodies such as the Purkinje cells of the cerebellum and pyramidal cells of the cortex. 3Scan’s current efforts include fluorescence imaging, neural reconstruction algorithms, antibody staining, and embedding. The impact of such technologies on cryonics, Huffman explained, would be in the form of an increase in conventional structural neuroscience data and the ability to reconstruct and evaluate procedures.

Sebastian Seung, Ph.D.

Day One of the conference ended with Sebastian Seung’s “Connectomics and Cryonics,” followed by a discussion of his talk. Seung began by explaining that connectomics is the application of techniques such as 3D imaging to build high-resolution maps of neural connections. The resulting map is known as the connectome. While working in the field at MIT, Seung met Alcor member and Harvard neuroscientist Kenneth Hayworth. When talking with Hayworth one day, Seung realized the implications of connectomics for cryonics and included some of his thoughts on the subject in his book Connectome, which elicited varied reactions.

Starting with the hypothesis that “you are your connectome” (reminiscent of “The Astonishing Hypothesis” of Francis Crick), Seung presented evidence from neuroscience that chemopreservation successfully preserves brain structure as evidenced by reconstructions using serial electron micrographs (EM). He then asked whether memories can be “read” from such connectomes and discussed what kinds of structural information might be important to answering such questions. Ultimately, he concluded that connectivity, including the shapes of neurons and locations of synapses, is what must be preserved in order to construct the identity contained within.
But Seung wonders how well cryonics preserves brain structure compared to chemical preservation methods.

To that end, Seung and Hayworth announced the Technology Prize to be awarded by the Brain Preservation Foundation to the first individual or team to demonstrate a technique capable of preserving a human brain for long-term storage with high fidelity. The current contenders for the first stage of the prize have employed both chemo- and cryopreservation methods, but the required imaging and analyses of these samples has not yet been completed. Seung’s presentation was followed by a relatively long discussion with the audience, which quickly turned into a debate about the merits of chemopreservation and cryopreservation. Topics discussed included the long-term stability of chemopreserved brains and whether the Technology Prize is neutral between both approaches.

Catherine Baldwin, M.S.

In her talk “From Bedside to Clinic: The Evolving Care of Cryopreservation Patients,” General Manager of Suspended Animation, Inc. (SA), Catherine Baldwin provided an overview of SA’s stabilization capabilities, which she described as “science, technology, and medicine in the service of cryonics.” Suspended Animation does patient recovery and stabilization for cryonics organizations, including Alcor. In fact, SA is contracted to perform standby and stabilization for all Alcor patients outside of the state of Arizona.

Baldwin described the stabilization and transport process, beginning with rapid induction of hypothermia followed by cardiopulmonary support (CPS) and administration of medications in preparation for the surgical procedure of cannulation to connect the circulatory system to the perfusion circuit. She stressed that the skills required to carry out these procedures are the same as you find in emergency and medical personnel.

Baldwin started recruiting EMS and surgical personnel early in her employment with SA. Because surgical and perfusion coverage is too expensive on a full-time basis, SA has contracted with companies that provide temporary coverage and now has four on-call cardiothoracic surgeons and eight cardiac perfusionists. Recently, SA has also contracted with a company that provides hospice and skilled nursing on-call. They also have 3 air transportable perfusion (ATP) kits and several vehicles supporting surgery (one on each coast).

In the future, Baldwin expects SA to roll out portable liquid ventilation, requiring only intubation to start efficient internal cooling using the lungs as a heat exchanger. Gene expression profiling is being explored to profile blood from patients using PCR. And finally, Baldwin thinks that by leveraging the network of professionals they’ve developed, SA will be able to build a network of clinical facility partners that will allow SA to start or carry out cryonics procedures within their facilities.

Aubrey de Grey, Ph.D.

The last segment of the conference focused on alternative theories of aging as argued by their primary proponents. First at bat was Aubrey de Grey, founder of Strategies for Engineered Negligible Senescence (SENS). De Grey believes that aging is the result of cumulative damage caused by normal metabolism. Pointing out that the presenters will disagree on some topics, de Grey stated that he thinks that damage does continue to accumulate in all
individuals no matter how old they get.

Traditional approaches to intervention in the aging process include gerontology (i.e., intervene between metabolism and damage to “slow it down”) and geriatrics (i.e., intervene between damage and pathology to “patch it up”). Both have been ineffective, and so we must consider another option – the maintenance approach.

The maintenance approach advocates repairing damage directly. It does not require understanding of complicated metabolic pathways leading to damage, but only how to repair the damage itself. “Not necessarily all of the damage,” de Grey says, “but enough of it to buy time so we can make it to the point that we can repair more of the damage.” His claim is that, unlike the others, the maintenance approach may achieve a big extension of healthy human lifespan quite soon and that it could help people who have reached middle age or older already.

To that end, SENS Foundation does research to implement SENS, including cell therapies and strategies to clean up extracellular “junk” that are in human clinical trials. And though some of these strategies alone have not achieved the clinical endpoints, de Grey believes that what is probably needed are combination therapies to address particular pathologies.

Joshua Mitteldorf, Ph.D.

“In 1997, everyone thought that free radicals were the cause of aging and that antioxidants were the cure. In 2012, we think it seems to be controlled by genes at a very high level and that signaling dysregulation is the problem.” Mitteldorf ’s hypothesis is that aging is not a result of dysregulation of some earlier homeostatic mechanism at all, but that it is programmed into us, and that “we live and die according to a schedule.”

He addressed four opportunities to preventing aging: (1) Preserving telomeres; (2) Damping inflammation; (3) Regulation of apoptosis; and (4) Restoring youthful gene expression.

Regarding the first strategy, Mitteldorf explained that telomeres are segments of “nonsense” at the ends of chromosomes that can be lost without causing any damage to the DNA. But DNA replication results in the shortening of telomeres over time, eventually resulting in cell death. An enzyme called telomerase, however, can add base pairs back to the chromosomes. The rationing of telomerase is a programmed death mechanism that evolution exploits to force the sharing of genes. In terms of pushing for telomerase therapies, Mitteldorf said he felt that “we’re ready for this” and that he felt very safe doing so. He discussed a number of (expensive) supplements that aim to activate telomerase.

Inflammation is an essential first-line defense against invading pathogens. In youth it is wholly beneficial, but as we get older our bodies begin to target healthy cells rather than just outside pathogens. All of the diseases of old age are associated with higher levels of inflammation. Some drugs that combat inflammation are cheap and easy, such as aspirin, omega-3 fatty acids, curcumin, and ginger. Other approaches to damping inflammation carry substantial tradeoffs, however.

Apoptosis, or cell suicide, is an ancient mode of programmed death found in even the earliest eukaryotes. When the body needs to get rid of diseased cells it does so through apoptosis. But apoptosis is also linked to diseases of old age, including Parkinson’s disease, sarcopenia, and glial cell loss. Strategies to limit apoptosis have very strong tradeoffs. We would need to find a way to make apoptosis “smart” so that it kills the “bad” cells and keeps the “good” ones.

Lastly, Mitteldorf discussed gene expression, which changes as we age. He explained that we do not have the same gene expression profile when we get older as when we were younger and that this makes for a very fertile area of research. There is a major effort underway to understand enough to manipulate the signals that determine gene expression, and if we are successful we may be able to restore youthful gene expression. “It may not be easy,’ Mitteldorf concluded, “but my dream is to slow aging from the top down.”

Michael Rose, Ph.D.

Rounding out the speakers on aging was Michael Rose, an evolutionary biologist who spoke on “How to Control Your Aging” (or “Looking Good in Liquid Nitrogen”).

Rose regards aging as “one of the most completely solved problems in science today.” He discussed the theory of the evolution of aging, explaining that some organisms don’t age at all and that eukaryotic molecular and cell biology allows for indefinite life without aging, but that “the force of natural selection acting on survival falls with adult age in animals like us.” The age of reproduction, he stated, is the key to aging. Experiments carried out in the 1970s delaying the first age of reproduction in fruit flies resulted in substantially slowing the process of aging across subsequent generations. This has allowed us to form a very powerful formal theory of aging.

Looking at other laboratory data, Rose indicated that experiments with medflies in the 1990s suggest that aging is only a transitory phase and that aging, in fact, ceases at some point in late life. After the cessation of aging there is a stabilization of some functional physiological characters while others continue to decline. The resulting plateau in late-life mortality is caused by the decline of natural selection.

Rose then argued that aging is not a cumulative process of deterioration, contrary to cell dogmas (and Aubrey de Grey’s platform). “Biological immortality evolves,” he said. “We’ve shown that aging stops at the level of the individual, we’ve shown that we can explain it evolutionarily, and we have experimental proof of such.” To control aging we must try to get immortal sooner – to cut off aging – and bring the aging plateau down to a younger age. Rose is interested in using environmental manipulation to effect this change.

Importantly, he asserted, the timing of cessation of aging depends on environment and lifestyle such as the food we eat. The key is to do what is natural for humans, or what we are adapted to. Rose argued that while young people of Eurasian ancestry are well-adapted to evolutionarily recent agricultural lifestyles, at later ages we progressively revert to physiology that is better adapted to the hunter-gatherer lifestyle.

To control your aging Rose suggests (a) adopt the hunter-gatherer lifestyle after 30- 40 years of age if Eurasian and earlier (10- 25 years) if ’your ancestry is less Eurasian, (b) use the best of modern medicine to lower your mortality level during the last decades of aging and during the plateau, and (c) use autologous tissue repair when it becomes available.

Panel with Mitteldorf, de Grey, and Rose

Wrapping up the conference was an interesting panel discussion with the three aging researchers, Mitteldorf, de Grey, and Rose, mediated by Greg Fahy. Each scientist had an opportunity to ask the others questions and to defend their respective theories in light of data they may not have addressed in their talks.

Mitteldorf wondered how Rose would model real societal changes that have large and lasting impacts on humans. Rose said that the Price equation attempts to take these changes into account, but that it is hard to model such things and that he “didn’t wish to underestimate the difficulty of this.”

Dr. Fahy then posed a challenge to de Grey and Rose: “Aubrey would say that metabolism is too complicated, and Michael would say something similar. But we’ve seen that knocking out ONE gene in C. elegans can increase lifespan by 10 times. How do you explain that?” Rose agreed that deleting even “one particularly bad thing” can have significant effects on longevity. “Evolution has already built life-history flexibility,” he said. “If you give up one of those major things, like building sperm, you will see great increases in lifespan.”

Aubrey de Grey clearly disagreed with Michael Rose and noted that the absence of natural selection does not mean the absence of accumulation of damage.

Many more technical arguments like this were exchanged, but at the end of the panel it became clear that there is no real consensus about what aging is and what would be the most efficient way to stop or reverse it.

Conclusion

In all, Alcor’s 40th anniversary conference was an enjoyable weekend for old and new Alcor members alike. The agenda was well-planned and the quality of speakers and presentations was very high. From the science of cryopreservation to the implications of neural network research on cryonics to strategies for preserving your assets as well as yourself, no stone was left unturned and no question unasked. We may not always have the answers, but with meetings like Alcor-40 stimulating discussion and ideas we can better determine where to look for them.

Cryonics, January 2013

By Aschwin de Wolf

Executive Summary

Scientific and practical considerations strongly support cryopreservation rather than chemopreservation for the stabilization of critically ill patients. Technology for achieving solid state chemopreservation of brains larger than a mouse brain does not yet exist. Chemical fixation is irreversible without very advanced technologies. Chemical fixation permits no functional feedback or development pathway toward reversible suspended animation. By contrast, cryopreservation seeks to maintain viability of the brain as far downstream as our capabilities and resources permit — an approach that reflects our view of cryonics as an extension of contemporary medicine. Cryopreservation preserves more options in that a cryopreserved brain could be scanned in future, or later chemically fixed, but the process of chemical fixation cannot be reversed and replaced by just low temperature storage. The cost benefits of chemopreservation over cryopreservation are exaggerated, largely because the standby and treatment procedures for effective chemopreservation would be just as extensive as for cryopreservation, if not more so, even assuming that highly toxic chemicals could be worked with safely in the field. Chemopreservation is being inherently tied to mind uploading, an association that is likely to limit its acceptance as a form of experimental critical care medicine by apparently requiring acceptance of the idea of substrate independent minds.

Introduction

The formation of the Brain Preservation Foundation and the recent publication of Sebastian Seung’s book Connectome [1] have given rise to a renewed interest in chemical preservation as a means of personal survival. Alcor welcomes these developments and has even attempted to donate to the Brain Preservation Technology Prize to stimulate validation of both cryopreservation and chemopreservation as preservation technologies [2]. In fact, in 2008 Alcor received a grant to conduct a preliminary investigation into chemopreservation [3]. In addition, Alcor staff member Mike Perry published an extensive article about lowcost alternatives for cryonics [4] and Aschwin de Wolf published the first technical review of chemopreservation as an alternative method of biostasis in Cryonics magazine [5].

A common denominator in our research and writings has been the recognition that chemical preservation may constitute a viable alternative to cryopreservation on a theoretical level but that scientific and practical considerations strongly support cryopreservation for the stabilization of critically ill patients. In this article we will further explore these issues and also respond to some of the recurrent arguments that have been made in favor of chemical brain preservation.

One seemingly paradoxical position that will be clarified in this article is that Alcor aims for better preservation technologies than can be offered through chemical preservation but is also more optimistic about the resuscitation of patients preserved under suboptimal conditions with older cryopreservation technologies.

Suspended Animation

What distinguishes the long-term objective of Alcor from chemopreservation proposals is that we are not satisfied with preservation of the ultrastructure of the brain alone. The aim of Alcor is to keep the patient viable by contemporary medical criteria as far into our procedures as possible [6]. There are a number of reasons for this choice.

The most important of these reasons is that restoring function after reversal of our procedures is the most credible test of the efficacy of our procedures. We are reluctant to settle for preservation of ultrastructure alone because this goal can always trigger objections that we are failing to preserve crucial identity-encoding parts of the brain. This is not just a theoretical concern. Recent discussions about chemical preservation of the “connectome” (pattern of connections between brain cells) have made it quite evident that absent functional recovery of the brain, there is no shortage of arguments that seek to show that chemical preservation will fail to produce the desired outcome. Some of these arguments invoke rather unorthodox views about how memory is encoded in the brain (such as the necessity of locking neurotransmitters in place) [7]. However, absent a test showing that memory is preserved after reversal of the preservation procedure, we will not be able to progress beyond a debate in which different perspectives compete without empirical resolution.

Another important reason why Alcor seeks to maintain viability of the brain as far downstream as our capabilities and resources permit is that we view cryonics as an extension of contemporary medicine and allowing unnecessary damage would contradict this perspective. Contemporary chemopreservation methods depend on extensive cross-linking of proteins and this cannot be reversed by contemporary medical technologies. In a sense, one could argue that chemopreservation has to “kill” the brain to preserve it. Although even in “ideal” cryonics cases we are not yet able to sustain viability throughout all parts our procedures, Alcor’s research efforts and resources are dedicated to attacking this limitation from all angles (rapid cooling during stabilization, development of low toxicity vitrification agents, intermediate temperature storage, etc.).

Yet another argument of seeking reversible preservation procedures is that we want to minimize the time the patient has to be retained in low temperature care. The shorter the period the patient has to be maintained in biostasis the less risk there is that social and financial challenges will force cryonics providers to discontinue care of their patients. Another benefit of minimizing injury prior to long term care is that earlier resuscitation may reduce the amount of alienation for the resuscitated patient.

Finally, a more general argument can be offered in favor of this approach. The conventional case for cryonics rests on the expectation that we (a) can cure the terminal disease the patient suffered from prior to cryopreservation; (b) will have available credible rejuvenation technologies to prevent the patient succumbing to another age-associated illness; and (c) will be able to repair the damage associated with the cryopreservation process itself. Since most of the scientific skepticism concerns the damage being done by biostasis methods themselves, eliminating this form of damage would further strengthen the case for human cryopreservation.

Reversible cryopreservation would constitute true suspended animation for humans. At Alcor we believe that a credible cryonics organization should aim for perfecting human suspended animation. If we can achieve reversible cryopreservation, the objection that our patients sustain too much damage in our procedures can be effectively countered and the remaining debate will be about the technical feasibility of rejuvenating the patient and restoring them to good health. As currently conceived chemopreservation is fundamentally incapable of securing viability of the brain and cannot be brought under the rubric of evidence-based medicine.

Our Friends in the Future

A common objection to cryonics has been that future generations may have little interest in resuscitating cryopreserved patients. At Alcor we do not want to rely solely on the goodwill of future generations and we have set a substantial amount of funding aside to deal with this issue ourselves. Still, the first thing we should recognize, as former Alcor President Michael Darwin has pointed out [8], that friendship should come from both sides. Preservation technologies that transfer many challenges and puzzles to people in the future may not make us many friends. If the term “friends in the future” has any meaning at all it should require minimizing the burden on future generations and even provide them an incentive for wanting to resuscitate us. This understanding informs Alcor’s decision to offer the best procedures possible and not to send off a compromised brain to an unknown future based on just a series of logical arguments.

Limits of connectome preservation

How do we know if our procedures are good enough? As discussed above, if we can demonstrate that a person (or relevant animal) can survive our procedures intact without loss of identity and memory, this will inspire confidence. But how can advocates of chemical preservation of the connectome know that what they are doing is good enough?

If one confines oneself to structural preservation of the connectome, it is always possible to object that “just” preserving the connectome is not enough. One could argue that we also would need to preserve detailed information about all different kinds of neurons, the molecular state of synapses (“synaptome”), ion channels, microtubules, neurotransmitters, extrasynaptic interactions and so forth. The most extreme position would be to argue that for meaningful brain preservation complete preservation of the brain (or a molecular brain scan) would be required. Now some of these objections can be countered by arguing that the biochemical basis for brain functioning and short-term memory does not need to be preserved to preserve the individual. But such arguments may not completely satisfy critics who believe there is more to identity preservation than the connectome. Without functional tests, biostasis proposals will remain a source of criticism for people who want more robust empirical corroboration for the efficacy of the proposed procedures.

The prevailing proposal is to subject an experimental animal brain to a series of procedures and then re-construct the brain through 3D imaging technologies. And here is where we think there is a formidable challenge for chemical preservation. Because functional tests are not possible in cross-linked brains, the only available reference for looking at the efficacy of chemopreservation is to compare the results of this procedure against images that have been obtained through chemical preservation as well! Granted, electron microscopy has taught us a lot about brain anatomy but we cannot say for sure whether the procedures employed to prepare specimens for electron microscopy (irreversibly) damage specific areas of the brain that are crucial for memory and identity. In neural cryobiology, on the other hand, it is possible to subject the cryopreserved brain tissue to both a viability test and (subsequently) to ultrastructural examination.

The response of people advocating chemopreservation as a means of personal survival is to supplement their arguments with a substantial amount of philosophy to make their point. But philosophical arguments are no substitute for empirical evidence and the only empirical evidence that will be persuasive to critical observers is to seek functional recovery. Absent that, cynics will continue to invoke the existence of some “platonic” fragile brain that no preservation technique can salvage.

The Brain Preservation Technology Prize

In 2010 the Brain Preservation Foundation established the Brain Preservation Technology Prize. The Prize seeks to validate chemical preservation and/or cryopreservation of the brain for personal identity preservation, and develop protocols to apply these technologies to large mammalian brains. Although the Prize is open to both chemical and cryobiological preservation methods, the endpoint for evaluating the quality of preservation involves advanced 3D electron microscopic imaging techniques. Obviously brain preservation technologies based on methods used to prepare tissue for electron microscopy (chemical fixation, staining and embedding) have a natural advantage when the evaluation method is electron microscopy. Cryopreservation methods are at a comparative disadvantage because they are designed to achieve different preservation objectives than preparation for electron microscopy. To succeed, Prize competitors using cryopreservation must successfully load cryoprotectant chemicals into a whole brain, cool to cryogenic temperatures, unload cryoprotectant chemicals, and then still perform the chemical preservation steps necessary to prepare tissue for electron microscopy. An advantage cryopreservation has is that Prize officials are permitting cryopreservation competitors to perform the chemical preservation steps on small tissue pieces after whole brain cryopreservation.

A specific concern for Brain Preservation Technology Prize competitors using cryopreservation is that cryopreserved brains are currently very dehydrated. Due to this dehydration, which typically persists even after cryoprotectant removal, it is not yet clear that cryopreserved brains can be effectively evaluated by the Prize organizers. To be specific, the criterion for success is preservation of the connectome, which requires two things: preservation of synapses and preservation of enough information to infer the pattern of connections between them. Neural cryobiology researchers believe that they can achieve good ultrastructural preservation of the brain but dehydration compactifies the neuropil, reduces space between structures, and makes the tissue so dark in the electron microscope that it is hard to actually observe the synapses. So if a quick scanning method doesn’t discern all synapses that are actually there, it will fail. There are techniques for doing electron microscopy at cryogenic temperatures in the vitrified state, but these depend on the tissue being sliced before vitrification. Making slices out of a whole vitrified brain while vitrified is a tough problem. It is easier to make thin slices out of a whole brain that’s been turned into solid plastic because the resin used is designed for being cut into thin slices for microscopy. So plastination has a natural advantage in this competition — in terms of processing for the tests rather than in actual results.

We have no doubt that the designers of the prize sought to design a neutral prize, but it is challenging to develop a prize that is truly neutral in term of evaluation. For example, if the prize used viability as a criterion, cryopreserved brains would be at a great advantage. In fact, the effects of using aldehydes and powerful oxidizers would render the chemopreserved brains dead by even the most charitable functional criteria. It is our belief that a prize that aims to corroborate the case for personal survival technologies should embrace both ultrastructure and viability.

What is plastination?

While the term chemopreservation has been used to describe the idea of chemical fixation as an alternative to cryopreservation, many proponents of the idea of chemical brain preservation use the more narrow term ‘plastination.’ Plastination is usually described as a technique first developed by Gunther von Hagens in 1977 to preserve body parts for anatomical or educational purposes. This is a rather “harsh” technique, which requires dehydration by alcohol and replacement of the lipids by a polymer. To our knowledge, there are no credible peer reviewed ultrastructural studies of brains plastinated in such a manner.

What most writers have in mind when they use the word “plastination” as a means of biostasis is a procedure in which chemical fixation with an aldehyde is followed by treatment with osmium tetroxide and resin embedding. While previous proposals for chemical brain preservation only discuss the use of fixatives such as formaldehyde to crosslink and immobilize proteins, the addition of osmium tetroxide and resin (plastic) embedding provide greater longterm stability. Osmium tetroxide stabilizes unsaturated lipids in the cell membrane, and replacement of cell water with a solid polymer resin stops diffusion of molecules in a manner similar to cryopreservation. While theoretically sufficient, the empirical sufficiency of these measures for preserving identity-critical information for centuries is not currently known, and may require complex accelerated aging studies. Another reason for including the two additional steps of osmium tetroxide fixation and resin embedding is to prepare the brain for slicing and scanning for resuscitation in the future.

Whatever “plastination” method is chosen, the consequence will be that the brain is rendered non-viable by contemporary medical criteria. In fact, chemical fixation and osmium tetroxide are routinely used with the explicit aim of killing life and irreversibly stopping biochemical activity.

The cost of chemical brain preservation

One of the proposed advantages of chemical preservation of the brain is to be its comparatively low cost compared to human cryopreservation. It can be admitted that an isolated chemically preserved brain reduces long term space requirements compared to a typical Alcor neuropatient. The space saving, however, is modest since the annual storage cost for a neuropatient is only a few hundred dollars per year. A chemically fixed brain can be removed from the skull and may not require a dedicated (low temperature) storage environment. In reality, however, we do not expect most people to be comfortable with the idea of long-term brain preservation without any kind of institutional structure. (Would you want your chemopreserved brain to be sitting unsecured on the shelf of a person who has no contractual obligation or means to protect you and eventually revive you?) So the real cost difference may more reflect reductions in storage space and long-term maintenance than elimination of organizations that protect these brains and initiate resuscitation.

Whether the cost of resuscitation of chemically preserved brains will exceed that of cryopreserved patients will depend on the method of resuscitation. If biological or mechanical cell repair machines are used to restore function, the costs of chemopreservation may actually be higher because the informational and logistical requirements of restoring a brain to its pre-cross-linked state may be even more daunting than that of a “straight frozen” brain. An alternative for brain repair is to slice the brain, scan it, and upload it to a computer. Such a revival scenario may be substantially less expensive than repairing a cryopreserved brain but it cannot be taken for granted that such revival attempts will constitute meaningful resuscitation of the individual. In addition, this method, destructive mind uploading, is possible for cryopreserved brains as well.

The expected cost of preparing the brain for long term chemical preservation cannot be separated from the issue of acceptance of the procedure. If chemical brain preservation is not accepted by mainstream medicine it will not be available as an elective hospital-based procedure. Like cryonics, chemopreservation should be practiced as a form of emergency medicine. As such, it will require the same kinds of “standby” and “stabilization” procedures to prevent post-arrest deterioration of the brain. In cryonics, professional teams capable of performing stabilization procedures rapidly and effectively cost tens of thousands of dollars to bring to the bedside. The cost to deploy teams to restore circulation and perfuse solutions after clinical death would be no different for chemical preservation, and they would be even more critical for preservation to be successful.

An additional complication for chemical brain preservation is the toxicity of the necessary chemicals to the team and surrounding personnel. In simple terms, chemicals powerful enough to bind and inactivate biological molecules must by their nature be very reactive and toxic to living people. (This is in contradistinction to chemicals used for cryopreservation, which are practically innocuous by comparison.) The initial steps of chemical preservation require perfusion with aldehyde fixative chemicals such as formaldehyde, glutaraldehyde, or acrolein. Even fumes of these chemicals at low concentration are powerful irritants to eyes and lungs. They could not be used in an ordinary hospital room or hospice setting. (Being similar to embalming fluid, aldehyde fixatives could possibly be used in a mortuary.) After initial stabilization with aldehyde fixatives, a chemopreservation patient would have to be transported to a dedicated facility for treatment with even more toxic chemicals such as osmium tetroxide and plastic resin monomers. Osmium tetroxide is a volatile and extremely powerful oxidizer, and epoxy resin monomers are mutagenic carcinogens. In addition to being very dangerous, these chemicals are also expensive and would bring the costs of chemical brain preservation closer to the costs associated with vitrification solutions in cryonics.

If chemical brain preservation were to be accepted as a routine hospital-based procedure, costs would be reduced because of economies of scale and the reduced need to deploy standbys and stabilize patients in the field. However, it is doubtful that one form of preservation would be accepted and the other would be rejected. As a consequence, if acceptance would reduce costs, this would happen to both chemical preservation and low temperature preservation of the brain.

The no-reflow phenomenon

One of our biggest concerns about offering chemopreservation as a practical means of stabilizing critically ill patients is that if the procedure is practiced in non-ideal circumstances, the effects could include progressive decomposition of brain tissue despite chemical fixation. In terms of tolerance of warm and cold ischemic delays, chemopreservation is a lot more demanding. Since the 1960s it has been recognized by many biomedical researchers that even short periods of warm circulatory arrest can produce perfusion impairment in the brain [9]. Any credible chemopreservation proposal requires access to the vessels of the patient. This means that in the case of delays due to warm and cold ischemia, there will be incomplete distribution of the fixatives. In fact, the recognition of this challenge is a standard part of textbooks on preparing specimens for electron microscopy.

Ischemia-induced “no-reflow” is a problem for both chemopreservation and cryopreservation, but even more so for chemopreservation. In the case of cryopreservation, incomplete distribution and equilibration of a cryoprotectant can produce ice formation, but long term care at cryogenic temperatures will stabilize the tissue with no further degradation. In the case of chemopreservation, the absence of low temperatures could permit ongoing degradation of poorly fixed and embedded tissue. While it is possible that resin embedding (solidification) would halt autolysis, the ischemia- induced perfusion impairment that prevents complete distribution of aldehydes would also prevent adequate perfusion of the organic solvents and monomers for resin embedding. (Whether resin embedding could be achieved by perfusion even under ideal conditions is still an open question.)

Chemopreservation as emergency medicine?

Even if chemical brain preservation would be accepted as a routine hospital procedure there will still be many cases in which this procedure will have to be applied on short notice outside of the hospital or after long delays. For example, people can experience sudden cardiac arrest in the street, die in their sleep, or be involved in a traumatic accident in a remote area. In these circumstances chemical preservation will have to be conducted after a (prolonged) period of circulatory arrest. As discussed above, delayed chemical fixation will most likely fail to completely fix all areas of the brain as a consequence of perfusion impairment. This major inadequacy of chemopreservation leaves cryopreservation as an irreplaceable biostasis technology for cases of unexpected cardiac arrest. Cold is the only biostasis-inducing agent that can rapidly penetrate tissue regardless of its state of injury.

Practicing chemical fixation as emergency medicine raises another complex logistical issue. One part of the procedures is to perfuse the brain with the dangerous chemical osmium tetroxide (or any other oxidizing agent that can stabilize lipids). We wonder whether it is possible to establish a protocol that would permit a safe environment to conduct this procedure in the field. While it is true that osmium tetroxide does not necessarily need to be administered in the field, and aldehyde fixation would buy enough time to transport to dedicated facilities, even the practice of emergency aldehyde fixation would create much greater health hazards than the practice of remote blood substitution in cryonics, or even field cryopreservation. As far as we are aware, even the most “toxic” solution used in cryonics (the vitrification agent) is less dangerous than the least toxic solution (formaldehyde and/or glutaraldehyde) envisioned for chemopreservation.

Solid state chemopreservation is not applicable to human brains at present

The clinical application of chemopreservation is still hypothetical because technology for fixing and plastic embedding whole human brains doesn’t exist yet. At the time of writing, the chemopreservation technology competing for the Brain Preservation Technology Prize uses external diffusion to introduce osmium tetroxide and resin into a mouse brain by soaking it in various solutions for more than 250 hours. Since diffusion time varies as the square of distance, a similar soaking protocol applied to a human brain would require six years. As a practical matter, such a protocol would almost certainly fail because of resin polymerization during the long soaking time. Rather than diffusion, perfusion protocols that circulate all chemicals through the vascular system appear essential for solid state chemopreservation of large mammalian brains. Such protocols have yet to be developed, and face considerable obstacles of viscosity and blood-brain barrier penetration.

The “Prehoda fallacy”

The impossibility of conducting functional assays in chemically preserved brains is one of our concerns and reflects our aim to develop technologies that are reversible with contemporary technologies. On the other hand, a dominant perspective in the advocacy of chemical brain preservation is that perfect preservation is a necessary condition for medical acceptance of cryonics or chemopreservation.

One of the most prevalent objections to cryonics among the educated public and scientists is that absent proof of reversible cryopreservation cryonics should not be offered to the public. One of the most outspoken representatives of this kind of reasoning was the author Robert Prehoda. In 1969 Prehoda published the book Suspended Animation: The Research Possibility That May Allow Man to Conquer the Limiting Chains of Time [10]. In this visionary book, he covered a variety of means to extend the maximum human life span including, but not limited to, chemical anabiosis, human hibernation, suspended animation, and controlling the aging process. Despite his participation in the 1967 cryopreservation of James Bedford (who is still a patient at Alcor) he was opposed to offering cryopreservation before the technology was perfected. He reiterated this stance in a 1969 interview in which he said: “I am still opposed, as I was before Dr. Bedford’s death, to freezing people at the present time because this money should be spent on research. Any human freezing is premature and without scientific basis until a mammal can be revived from the frozen state” [11].

Prehoda’s objection to offering cryopreservation continues to be made in either a strong or a weak version. In its strongest form it is argued that it is not “scientific” to offer cryonics services as long as reversible cryopreservation of a whole mammalian organism has not been demonstrated. Such claims are often presented in the form that there is no scientific “proof ” that cryonics will work. A weaker version of the argument also exists in which it is claimed that without evidence of reversible cryopreservation the general public and scientists have good reason to reject it.

These views rest on a fundamental misunderstanding of the rationale of cryonics and do not recognize the distinction between the objective of science and the objective of medicine. The objective of science is to generate knowledge about the physical world by testing hypotheses. The objective of medicine is to treat people (or non-human animals) by using the best knowledge from science and practical experience available. Medicine is inherently “messy” because it cannot avoid acting on incomplete information in conjunction with a (subjective) assessment of risk. For example, if a person is in overall good health most people would not support subjecting this person to an experimental treatment with potential severe adverse effects for a minor illness. On the other hand, if a person is born with a highly lethal single gene mutation, more risky experimental treatments could be justified. What distinguishes cryonics from conventional medicine is not decision making under uncertainty but the temporal separation of stabilization and treatment.

Evidence-based medicine is inherently conservative and the idea of cryonics extends this conservatism to end-oflife decisions. The fact that society has exhausted all means of curing critically ill patients does not mean that future medicine will not be able to treat this patient. The objective of cryonics is to ensure that a patient is stabilized to reach that future with as little additional damage as possible. The fact that current cryopreservation methods are not reversible and cause (additional) damage cannot be used as an argument against this reasoning because the argument that treatments may be available for presently terminal illnesses can also be extended to cover the damage associated with the cryopreservation process. The “Prehoda fallacy” consists of not recognizing the point that a procedure that aims to take advantage of future developments in science by definition cannot be experimentally demonstrated by contemporary science. Exercising our best judgment in this matter is neither “scientific” nor “unscientific” although one can question whether the reasoning involved is coherent or not.

This of course does not mean that science should not play a role in making such decisions. Certainly it should. The cryonics proposal can be submitted to the test of whether it contradicts known laws of physics or exceeds realistic computational abilities required for cell repair. More specifically, reasonable expectations about future medicine can be strengthened by improvements in cryopreservation or cell repair technologies. And, of course, we can generate experimental evidence to choose between alternative biostasis methods such as the use of cold temperatures or chemical fixation. But ultimately, cryonics cannot be “proven” in the conventional sense of the word because if all components of the proposal (curing the terminal disease, reversing cryopreservation, and rejuvenation) could be demonstrated now, cryonics would be redundant. We can make efforts to minimize this element of uncertainty but eliminating it completely may never be possible as there may always be diseases and traumatic insults that contemporary technologies cannot treat. In this sense, the acceptance of uncertainty in conjunction with reasonable expectations about future technological development is an intrinsic element of cryonics.

The reason why we highlight this fallacy is that we have observed a milder form among advocates of chemical brain preservation. Although lip service is being paid to the rationale of cryonics, the argument seems to be that technical feasibility is an important reason for scientists to reject cryonics. Such a perspective seems quite reasonable but it fails a basic reality check. Most scientists who comment on cryonics in public have made little effort to educate themselves about the procedure and often make uninformed statements about cryobiology and the ultrastructural effects of cerebral ischemia that even contradict the established knowledge in those fields of research. And when cryonics organizations introduce new procedures (such as vitrification) that aim to eliminate a scientific objection, the criticism simply moves to another part of the procedure. The residual element of uncertainty that characterizes cryonics can always be exploited to claim that the procedure lacks scientific proof. Eliminating ice formation or fracturing, or demonstrating preservation of the connectome will not satisfy critics who use these kinds of arguments to shield more subjective psychological and social objections to cryonics. Successful preservation of the connectome may win over some doubters but it is not likely that it will move chemopreservation and/or cryonics into the mainstream until these psychological and social objections can be effectively countered.

What constitutes preservation?

Insistence on demonstrated preservation of the connectome as a condition for offering a bio-preservation method to the terminally ill could backfire. Actually, we don’t know if the connectome is either necessary or sufficient. As long as it, and whatever else that is essential, if anything, can be inferred from the preserved brain (and the rest of the body) restoring the original healthy state should be possible [12]. This argument does not just apply to biostasis procedures that introduce known and predictable forms of damage but also applies to any patient who suffers some degree of ischemia prior to preservation. In fact, a perfect preservation of an ischemic brain might be classified as not being successful if it does not conform to the preservation of the connectome of a control brain. But whether this dooms such preservations to failure depends on whether the original state can be inferred from what was preserved, which itself is a function of the degree and duration of ischemia.

We believe that a research program aimed at demonstrating under which conditions the original structure can be inferred from the injured brain could be at least as persuasive as a program to demonstrate successful preservation of the connectome of noncompromised brains. Demonstrating the scope and limits of such reconstructions will also corroborate the premise of cryonics that using a preservation technique that itself adds damage is not necessarily a dead end provided there is systematic knowledge of how this preservation method alters the structural and functional properties of the brain.

Neural archeology and suspended animation

There is a wide gap between the aim of moving toward reversible human cryopreservation and the state of the brain of many cryopreservation patients. It might be tempting to conclude that a commitment to developing true human suspended animation implies a pessimistic outlook on the prospects of resuscitating patients that were preserved under suboptimal conditions with older technologies. In our view, such a perspective ignores the important point that one can aim for the best preservation technologies possible but at the same time hold that advanced “neural archeology” might be able to infer the original state from a brain with severe damage [13]. What makes Alcor’s perspective unique is that we share both the belief that our procedures should be subjected to the most rigorous testing possible with the goal of perfecting preservation technologies but that we also recognize that our understanding of the limits of “inferability” will remain incomplete as long as our scanning, computational, and repair technologies evolve. There is no question that providing the best technologies that we can offers the best prospects of resuscitating our patients in the future but this argument cannot be used to categorically claim which patients are beyond repair and which are not [14]. In our opinion, the perspective that informs many advocates of chemopreservation sets the bar too low and too high.

Are there advantages to chemical brain preservation?

One of the envisioned advantages of chemopreservation over cryopreservation is that plastinated brains do not require continued maintenance or even organizational continuity. This may be true but there are a number of qualifications that need to be discussed. As discussed above, this advantage only applies to brains that were preserved under ideal conditions. In non-ideal conditions, the brain will most likely experience regional or global autolysis over time. Strictly speaking, we do not even know anything about the fate of wellpreserved brains after very long periods of time and it might still be the case that even these brains benefit from storage at low (non-freezing) temperatures.

While it is technically feasible that such brains do not need a permanent storage facility like cryonics patients, it is hard to imagine chemopreservation being offered without the existence of an organization that is committed to the fate of such patients and maintains sufficient funding for future resuscitation attempts.

It cannot be denied that cryopreservation patients require ongoing replenishment of liquid nitrogen to keep them at low temperatures but this does not mean that cryonics patients would be adversely affected by short interruptions of liquid nitrogen deliveries. Calculations at Alcor predict that it will take at least three months of non-delivery of liquid nitrogen before the brains of patients would start dangerous warming. If such a scenario is due to supplier unavailability (such as a refusal to deliver to Alcor) Alcor could purchase and transport liquid nitrogen from elsewhere, start producing liquid nitrogen itself, or (temporarily) switch to other means of maintaining cryogenic temperatures.

In case cryonics patients cannot be maintained in dewars at all, emergency chemopreservation will be an option. This can be achieved by either perfusing the formerly cryopreserved patients or by slicing the brains and using passive diffusion to chemically fix them.

The most negative scenario would be a prohibition of cryonics and forced burial of patients. While not impossible, it is doubtful that in such an environment chemically fixed brains will be permitted to exist. Both cryopreservation and chemopreservation would have to continue as underground operations.

Chemopreservation and mind uploading

One of the lessons that we have learned in cryonics is that it is not helpful to make the idea more controversial than necessary. Cryonics (or chemical brain preservation) is already controversial enough on its own and we do not see the benefit of associating it with ideas such as immortalism, transhumanism, mind uploading, or any political ideologies. This is not just a strategic or public relations consideration but reflects our view of offering cryonics as a form of experimental critical care medicine.

In many ways the promotion of chemical brain preservation has been characterized by many of the PR mistakes that characterized the beginning of cryonics. In particular, we are concerned that, instead of remaining agnostic about resuscitation methods including mind uploading, chemical brain preservation is now closely associated with this one method.

There is something decidedly ad hoc about this association. One could just as well imagine a campaign for chemical brain preservation that identified mechanical or biological cell repair technologies as the means of resuscitation. What is unfortunate about the almost exclusive focus on mind uploading is that it not only requires potential supporters to take seriously the idea of chemical preservation of the brain but also commit to the idea of substrate independent minds.

It is no surprise that the defense of mind uploading depends on mainly philosophical arguments because at this point these are the only possible arguments to defend it. While the arguments in favor of mind uploading deserve critical scrutiny, we think that ultimately the feasibility of this approach is an empirical matter and cannot be settled by thought experiments or analogies [15] For example, both proponents and skeptics of mind uploading accuse each other of not being consistent “materialists.”

In fact, by subjecting the preservation method to empirical scrutiny but using philosophical arguments to corroborate the resuscitation method, we think that the Brain Preservation Foundation conveys a mixed perspective about validation of personal survival technologies. The kinds of cell repair technologies that are envisioned for the resuscitation of cryonics patients are highly advanced, but do not require a shift in thinking about human biology and identity. Mind uploading, on the other hand, is neither conceptually necessary for resuscitation of chemically preserved brains nor does it constitute an appealing idea to gain more support for chemopreservation.

Toward a new definition of death

In this article we have critically investigated the claims in favor of chemopreservation, and its (envisioned) advantages over cryopreservation. While, everything carefully considered, we believe that cryopreservation is more suitable for robust scientific validation and presents a more versatile, practical, and safe option than chemical brain preservation, we strongly support any technologies that draw attention to the inadequacies of contemporary practices surrounding death. Throughout history the medical definition of death has been subject to continuous revision as medical and resuscitation technologies have advanced [16] There can be no doubt that many people who are written off by today’s medicine will simply be considered critically ill in the future [17] Both cryonics and chemical brain preservation constitute a means to stabilize patients to reach that future. In the coming years we may see additional proposals to stabilize critically ill patients such as “room temperature vitrification” or biostasis induced by advanced nanotechnology. Clearly, the idea that death should be defined relative to today’s medical capabilities is no longer adequate and needs to be replaced by a concept of death that recognizes that clinical death can only be considered irreversible if identity-critical information has been erased beyond recognition [18].

This article greatly benefited from the encouragement and contributions of Max More and Brian Wowk. I also want to thank the Alcor R&D Committee for carefully reviewing earlier versions of this article.

Update

The original paper version of this article included the results of an experimental model to understand the effects of ischemia on perfusion fixation of the rat brain. Subsequent comments and questions prompted me to omit them from the current (online) version because these results raise complex methodological issues about modelling perfusion fixation of the ischemic human brain in a rat model and I believe that those cannot be done justice without changing the nature of the article. I wish to convey that these results are part of an ongoing research project and using them as an illustration of the potential consequences of conducting perfusion fixation in the ischemic human brain would be premature. Excluding these preliminary results does not affect the general arguments made in this article and restores its intended aim as an opinion piece. Omitting them should not be interpreted as an endorsement of the idea of perfusion fixation of ischemic human brains as a life extension strategy.

Appendix: Resin Embedding of Mouse Brains

In 2012 a group from the Max-Planck Institute for Medical Research in Germany published a method for resin embedding an entire intact mouse brain suitable for electron microscopy [S. Mikula, J. Binding, W. Denk, Staining and embedding the whole mouse brain for electron microscopy, Nature Methods, published online 21 October 2012; doi:10.1038/nmeth.2213]. This group is also one of the announced competitors for the Brain Preservation Technology Prize. Their recently-published method may qualify for the Stage 1 (small brain) portion of the Prize.

They achieved a technical tour-de-force because a mouse brain is much larger than the tiny milligram size previously required for tissue pieces to be prepared for electron microscopy. However their basic approach is still the same as traditional methods for preparing small tissue pieces. First, proteins are chemically fixed by perfusing an aldehyde solution through the whole animal. Second, the brain is removed and then soaked in solutions containing osmium tetroxide to fix and stain membranes. Third, the brain is soaked in organic solvents to replace water. Finally the brain is soaked in solutions of resin monomer molecules that eventually polymerize, turning the tissue completely solid.

Except for the first protein fixation step, this approach relies completely on passive diffusion (soaking) rather than perfusion. According to the paper, to resin embed a mouse brain, the time required for the soaking steps is:

5 x 8 hours (buffer rinses)
3 x 48 hours (wbPATCO osmium stain)
4 x 12 hours (acetone dehydration)
3 x 12 hours (resin monomer infiltration)
———
268 hours total

Calculation of the time that theoretically would be required to perform these steps on a human brain is sobering. A human brain is 1500 grams / 0.5 grams = 3000 times more massive than a mouse brain. Taking the cube root of 3000, that translates to 14 times greater diameter than a mouse brain. Using the rule that diffusion time scales quadratically with distance, the extrapolated preparation time for a human brain would be

14 x 14 x 268 hours = 52,528 hours

which is six years. In practice, the process would likely stop early in the resin soaking phase as monomers polymerized in the outer layers of the brain, increasing viscosity and preventing deeper infiltration.

Development of fundamentally new technology – technology using perfusion for all phases – is required before resin embedding can be seriously considered for biostasis of large mammalian brains.

References

1. Sebastian Seung, Connectome: How the Brain’s Wiring Makes Us Who We Are, Houghton Mifflin Harcourt Trade, 2012. See also Aschwin de Wolf ’s review in Cryonics magazine, September-October, 2012.
2. “Alcor Donation to Brain Preservation Technology Prize Declined”: http://www.alcor.org/blog/?p=2629
3.  See “Alcor Administrative Report,” January 25, 2008: http://www.alcor.org/blog/?p=163
4. Michael Perry, “The Road Less Traveled: Alternatives to Cryonics,” Cryonics magazine, 3rd Quarter, 2007, Volume 28:3
5.  Aschwin de Wolf, “Chemopreservation: The Good, the Bad and the Ugly,” Cryonics magazine, 4th Quarter, 2009.
6. Aschwin de Wolf, “Securing Viability of the Brain in Cryonics,” Cryonics magazine, 2nd Quarter, 2007.
7.  Michael G. Darwin, “Ray Kurzweil on Memory and Cryonics,” Cryonics magazine, November-December, 2012.
8.  Michael G. Darwin, “Postmortem Results: Some Perspectives,” Cryonics magazine, September, 1984.
9. See Majno G, Ames AIII, Chiang J, et al. “No reflow after cerebral ischaemia,” Lancet. 1967; 2: 569–570 and Ames III A, Wright RL, Kowada M, et al. “Cerebral ischemia, II: the no-reflow phenomenon,” Am J Pathol. 1968; 52: 437–447.
10. Robert W. Prehoda , Suspended animation: the research possibility that may allow man to conquer the limiting chains of time, Chilton Book Co., 1969.
11.  “Interview with Robert W. Prehoda,” first published in Cryonics Reports, Vol. 4, No. 1, January, 1969. Online: http://www.evidencebasedcryonics.org/interview-with-robert-w-prehoda-1969/
12. Aschwin de Wolf, “Preserving and Inferring,” Cryonics magazine, September-October, 2012.
13. Thomas Donaldson, “Neural Archeology,” Cryonics magazine, February, 1987.
14. Brian Wowk, “Ethics of Non-Ideal Cryopreservation Cases,” Cryonics magazine, Fall, 2006.
15. “Can You Build a Locomotive Out of Helium? Robert Ettinger on Substrate-Independent Minds,” Cryonics magazine, 4th Quarter, 2011 and Patrick D. Hopkins, “Why Uploading Will Not Work, or, the Ghosts Haunting Transhumanism,” International Journal of Machine Consciousness, Vol. 4, No. 1 (2012).
16. Steven B. Harris, “The Society for the Recovery of Persons Apparently Dead,” Cryonics magazine, September, 1990.
17. Max More, “The Terminus of the Self,” Chapter 2 of The Diachronic Self: Identity, Continuity, Transformation, doctoral dissertation 1995, http://www.maxmore.com/chapter2.htm.
18.  Ralph C. Merkle, “The Technical Feasibility of Cryonics,” Medical Hypotheses 39(1992):6-16.

Cryonics, November-December 2012

As evidence is emerging that contemporary vitrification technologies are adequate to preserve identity-critical information in the brain, critics of cryonics have tried to raise the bar by postulating that the neuroanatomical basis of memory is so fragile and transient that it cannot be captured by technologies that can successfully preserve the connectome. The online exchange that gave rise to this article is 10 years old but the topic has renewed relevance again (editor).

By Michael G. Darwin

Following the Alcor 2002 Fifth Alcor Conference on Extreme Life Extension, Eric Drexler, Robert Bradbury and Ray Kurzweil discussed the question of what would be required to achieve successful recovery of a fully functioning human brain from cryopreservation with intact mentation and memories.  This email dialogue was sparked as a result of the recent Alcor Conference on Extreme Life Extension.

 One of the most interesting and, for me, certainly one of the most memorable quotes from that discussion was this assertion by Kurzweil:

 “It’s the third requirement that concerns me; the neurotransmitter concentrations, which are contained in structures that are finer yet than the interneuronal connections. These are, in my view, also critical aspects of the brain’s learning process. We see the analogue of the neurotransmitter concentrations in the simplified neural net models that I use routinely in my pattern recognition work. The learning of the net is reflected in the connection weights as well as the connection topology (some neural net methods allow for self-organization of the topology, some do not, but all provide for self-organization of the weights). Without the weights, the net has no competence.”

This quote is memorable, and surprising, because it demonstrates an inaccurate understanding of the neurobiology of memory and learning. There are certainly many things we do not know about how long term (or short term) memories are encoded in the physical structure of the brain. However, there are some things we can pretty much rule out, and the ideas put forth by Kurzweil (and not immediately criticized by Drexler and Bradbury) are among them.

It thus seems pretty clear that within the cryonics scientific community some serious education needs to take place and, to that end, let’s dissect Kurzweil’s statement.

What are neurotransmitters (NTs) and how is their concentration in brain synapses determined?

Simply put, NTs are chemicals released at the synaptic junction which are responsible for not just the transmission of signals across the synapse, but for the “strength” of the signal transmitted. Thus, they serve a “weighting function” to signaling. How much NT gets made or released is NOT a function of the NT itself, anymore than how much smoke gets released from a fire being used to send smoke signals is a function of the smoke. NTs are smoke, they are the signal medium, not the signal itself, or the source of signal, or the signal’s strength.

Focusing on the conservation of NT levels in synapses as the key to the preservation of memory is analogous to focusing on the smoke in a smoke signal as the durable element of the underlying data set. Neurotransmitters are the smoke, the real question is, what causes the NTs to be made and released in predictable amounts and ways over long periods of time. In other words, who is controlling the amount and pattern of smoke release in a smoke signaling operation?

Simplified schematic of the expression of LTP: An increase in calcium within the dendritic spine binds to calmodulin (CaM) to activate CaM Kinase II, which undergoes autophosphorylation, thus maintaining its activity after calcium returns to basal levels. CaMKII phosphorylates AMPA receptors (AMPARs) already present in the synaptic plasma membrane, thus increasing their single-channel conductance. CaMKII is also postulated to influence the sub-synaptic localization of AMPA receptors, such that more AMPA receptors are delivered to the synaptic plasma membrane. The localization of these “reserve” AMPA receptors is unclear, and thus they are shown in three different possible locations. Before the triggering of LTP, some synapses may be functionally silent in that they contain no AMPA receptors in the synaptic plasma membrane. Nevertheless, the same expression mechanisms would apply.

The current consensus in the field of the neurobiology of learning and memory is that there is extensive biochemical change in the synapse itself, probably beginning with a process called Long Term Potentiation (LTP):

Beyond that, many questions abound. It seems clear that in addition to biochemical changes in the synapse, there are also changes in the number and in the physical type and configuration of the synapses that occur during learning and memory encoding:

Most synapses cover a small area and have a compact, roughly convex shape, such as numbers 51, 59, and 81, above. These are referred to as macular synapses. Larger synapses often exhibit ‘holes’ in the middle. These holes are regions of cell membrane devoid of the specializations characteristic of the synapse, e.g. postsynaptic density, synaptic cleft, presynaptic active zone. Synapses with holes, such as numbers 45, 46, 86, 90, 94, 96, and 100, are referred to as perforated synapses. Of the 161 synapses so far classified in the neuropil, 148 are macular, while the remaining 13 are perforated. The difference between macular and perforated synapses can be seen in electron micrographs in which the postsynaptic densities have been stained

There are well over 140 different physical TYPES OF SYNAPSE and the myriad new connections that form during learning may use many different synaptic morphologies. What’s more, sometimes many of the synapses that initially form during encoding of learning, especially multiple synapses on the same dendrite, are pared down or disappear during what is believed to be the consolidation phase of memory encoding.

Reconstruction of ‘same-dendrite, multiple synapse boutons’ (sdMSBs) and related structures in a hippocampal brain slice. (a) The sdMSB makes a synapse with the head of one spine (x) on this section. Three of the axons (4,6,7) are visible between the spine head and the dendrite (Dend). (b) Three-dimensional reconstruction of the dendrite (gray), the sdMSB axon, and all seven axons (1–7) passing through the gap between the spines (x,y). Four of the axons (2,4,5,6) are cross-sectioned to avoid obscuring the other axons. Scale bar, 0.75 μm. [Fiala JC, Allwardt B, Harris KM. Dendritic spines do not split during hippocampal LTP or maturation. Nat Neurosci. 2002 Apr;5(4):297-8. PubMed PMID: 11896399.]

Now the really interesting thing is that synapses are not transient fluctuations in the level of a biochemical, or signaling molecule – they are complex structures made of protein and protein gets made (and maintained) only as result of signal transduction between the cell nucleus and the ribosomes: DNA > RNA > ribosomes > protein. Indeed, even the synaptic vesicles and the neurotransmitters inside them, are manufactured in the cell bodies and subsequently transported to the synapses (the “right” synapses) – all of which is presumably under nuclear control. Since memories persist at least a century in humans, it is clear that the biological structure(s) that encodes them is durable and well maintained. Put another way, the mechanism that controls and determines the pattern of smoke signaling is both robust and durable.

That’s where things get hazy about how long term memory is preserved.

Our current understanding of the gating mechanisms of synapse firing suggests that the character, quantity and configuration of synapses is how memory “works,” or is encoded. But what we don’t know is how the instructions to maintain those synaptic configurations are initially activated and ultimately encoded in the neuron itself.

At this point, it should hopefully be clear that in theory, it should be possible to recover a brain with memories and personality intact, even if there was not a single molecule of NT present in any synapse, anywhere. The NTs are MADE by the neurons and released by the synapses in the “right” amount at the “right” time and in the “right” way as a function of the UNDERLYING synapse and nerve cell structure. Not the other way around!

Since I spent a good part of my adult life wrestling with the problem of ischemia-reperfusion injury in the mammalian brain, I would be remiss if I did not point out that in ischemia, NTs leak out of the boutons in the synapses. In the case of the excitatory NTs, such as glutamate, the superabundance of NTs that are present when circulation is restored causes enormous injury. The point is that NTs aren’t stable and don’t sit around in synapses without active pumping going on (requiring metabolism). They leak out rapidly under conditions of ischemia and hypoxia. And yet, if the animal or person survives (along with their brain cells), they still have intact long term memories. The neurons simply re-synthesize and replace the necessary synaptic vesicles/boutons containing the requisite types and amounts of NTs.

The question that should be preoccupying cryonicists is whether there are sufficient intact neurons and synapses present to be preserved in the first place – not whether or not the NTs levels are conserved in synapses following cryopreservation.

A scientifically sound and considerably more rigorous discussion of the issue of whether memory (and personal identity) survive cryopreservation can be found here.

Cryonics, November-December 2012

By Aschwin de Wolf

The cryonics organizations Alcor and the Cryonics Institute have taken great care to correct some of the persistent myths about cryonics. With so much widespread misinformation being circulated in the media it seems trivial to pay attention to some of the misconceptions that some people who are sympathetic to cryonics hold. But the price of ignoring these opinions is that progress in the science of cryobiology and practice of human cryopreservation is adversely affected. What follows is a list of 5 “dangerous” ideas (or misconceptions) about cryonics and their consequences.

1. First in, last out.

A popular expression in cryonics is that the first person who was cryopreserved will require the most extensive repair technologies and therefore will be the last person to be resuscitated. The underlying assumption in this view is quite reasonable: when advances in cryopreservation technologies are made, demands on advanced future repair technologies will be lessened. The problem with this view, however, is that it assumes that advances in cryobiology and neuroprotection are the only factor influencing the quality of care in cryonics. Unfortunately, advances in the science of cryopreservation will not automatically translate into better patient care.  Other factors, such as the delay between time of “death” and start of procedures, and the protocols, equipment and personnel of the responding cryonics organizations, matter as well. For example, if a cryonics standby team is not able to get to a patient before 24 hours after cardiac arrest, pumps him full of air during remote blood washout, and ships him back to the cryonics organization at subzero temperatures, that patient will not benefit from advances in human cryopreservation such as rapid induction of hypothermia, neuroprotection and vitrification.

A professional cryonics organization with “old” technologies may on average do better than an incompetent cryonics organization with “new” technologies. The important lesson to be drawn here is that the concept of “patient care” is a meaningful concept  in cryonics and consumers of cryonics services need to evaluate their cryonics providers on their ability to provide good care.

2. Only the future will tell us how good our cryonics procedures are.

It is true that only the future will tell us whether cryonics patients will be resuscitated or not; but that does not mean that we cannot say anything meaningful about the quality of care in individual cryonics cases. The most obvious point is that we can compare actual patient care to the published protocols and objectives of the cryonics organization. More specific observations can be made during a cryonics case using medical equipment. In a well-run cryonics case a number of physiological and chemical measurements are made to determine the response of a patient to various interventions. As a general rule, the objective of cryonics stabilization procedures is to keep the brain of the patient viable by contemporary medical criteria. The danger of thinking of cryonics as one single experimental procedure that can only be evaluated in the future is that it ignores the fact that actual cryonics procedures consist of various separate procedures that can be monitored and evaluated using existing medical tools. The least that a cryonics consumer should expect from his cryonics organization is that it discloses its cryonics procedures to the general public and produces detailed case reports.

3. Cryonics patients are no longer being frozen.

Because not all cryonics patients will be “ideal” cases, this view is vulnerable to the same objections as the “first in, last out” rule, but there are some other issues that are important to mention in this context. The most important fact to be stressed is that ice formation is not a binary all or nothing thing but a continuum ranging from straight freezing (cryopreservation without cryoprotection) to complete elimination of ice formation. Although there have been many cases where patients have been frozen without the use of a cryoprotective agent, its opposite, complete vitrification, should be considered  a theoretical ideal. The degree of ice formation is determined by the nature and concentration of the cryoprotective agent. For example, low concentrations of the cryoprotectant glycerol will result in more ice formation than higher concentrations of glycerol.

What has changed in recent years is that both major cryonics organizations are now offering cryopreservation using vitrification agents. Although these agents are formulated to eliminate ice formation, it is generally believed that such a result is not achievable in all tissues and organs in the human body at the moment.  Another important point to be made is that not all solutions that can eliminate ice formation are equal because they can differ greatly in toxicity.  The technical challenge in cryonics is not so much to eliminate ice formation but to develop vitrification solutions with no or limited toxicity. Although it is correct that contemporary vitrification solutions  can solidify without ice formation, delays in response time, poor patient care, and high toxicity can offset most of these advances.

4. The probability that cryonics will work is X.

Both critics and supporters have made specific probability estimates about how likely cryonics is to work. In its worst form such probability assessments convey nothing more than putting a number on overall feelings of pessimism or optimism. More serious attempts have been made to calculate a specific probability that cryonics will work. Such attempts usually go as follows: A number of independent conditions (or events)  for cryonics to work are distinguished, these conditions are “assigned” a probability, and the total (or joint) probability is calculated by multiplying them. Although such calculations give the semblance of objectivity, they are  equally vulnerable to the fundamental objection that assigning one single number to the probability that cryonics will work is just a lot of hand waving.  How many independent events are there and how do we know that they are independent? What is the basis for assigning  specific probabilities to these conditions? What are the effects of minor changes in the numbers?

Probability calculations are not completely useless.  They can help us in identifying important conditions that need to be satisfied for resuscitation. They can also help identify weak links  that can be improved. But probability estimates can be dangerous as well when we take them too seriously and discourage people from making cryonics arrangements. The point here is not that we should refrain from being skeptical but that if we make quantitative estimates we should be able to back up our statements with rigorous arguments or just confine ourselves to more qualitative statements. Another objection to making cryonics probability estimates was made by the cryonics activist and mathematician Thomas Donaldson. He makes the common sense point that many of these conditions are not independent of what we do. We can make a contribution to increasing the probability that cryonics will work.

Last but not least, what does it mean when we talk about “cryonics working?” It is conceivable that cryonics will work for one person but not for another, reflecting improved technologies and protocols. Perhaps asking the question if cryonics patients can be “revived” is the wrong question. As the cryobiologist Brian Wowk has pointed out, the real question is how much original personality would survive the many possible damage/repair scenarios, not revival per se.  Survival in medicine is not a simple black-and-white issue, as evidenced by people who recover from stroke or cardiac arrest but with personality and memory alterations.  And it is worth  mentioning once more that how much of our personality survives depends on what we do to improve the quality and long-term survival of our cryonics organizations.

5. I will sign up for cryonics when I need it.

It should be obvious without much reflection why this is a dangerous idea. At the time a person really needs cryonics, he may no longer be able to communicate those desires, lack funding to make arrangements, or encounter hostile relatives. A more subtle variant concerns the person who expects that aging will be solved before cryonics will be necessary. This person may or may not be right, but such optimism may not make him more immune to accidents than other people. This mindset is often observed among young “transhumanists” and practicing life extensionists. A related, but rarer, variant is to postpone making cryonics arrangements until the cryonics organization makes a number of changes including, but not limited to, hiring medical professionals, stopping wasting money, becoming more transparent, giving members the right to vote, etc. Such issues are important, and need to be addressed, but a safer response would be to join the organization and influence its policies, or, if this proves necessary, combine with others to start a competing cryonics organization without such flaws.

There are not many people who think that it is sensible to make cryonics arrangements, but there are even fewer people who have actually made such arrangements.

As we have seen, some of these dangerous ideas share the same or related assumptions and produce identical effects: decreased scrutiny of cryonics organizations and a decreased chance of personal survival. An important common theme is that cryonics cannot be treated as one single monolithic technology and that the fate of our survival depends as much on the state of the art in human cryopreservation technologies as on the competence of cryonics providers. Caveat emptor!

Originally published in January 2009 on the cryonics blog Depressed Metabolism.

Cryonics, September-October 2012

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

Reviewed by Aschwin De Wolf

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

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

Cryonics, September-October 2012

By Ben Best

On Saturday, July 7, 2012, I attended the Symposium on Cryonics and Brain-Threatening Disorders in Portland, Oregon. The symposium was the “brain child” of Aschwin de Wolf, who also kindly invited me to give a presentation on treatments to mitigate Alzheimer’s Disease (AD). The symposium was organized by the Institute for Evidence-Based Cryonics and Cryonics Northwest.

It has been said that cryonics arrangements are made by people who think about things other people would rather not think about – in this case, one’s personal mortality. Like the sun in the sky, we can be aware of its presence, but prefer not to look at it. Dementia is in the same category. Despite the fact that anyone who lives long enough (cryonicists are usually life-extensionists) is much more likely than not to get dementia, even cryonicists are often reluctant to plan for becoming demented. Aschwin deserves a lot of credit for not only being a cryonicist, but for organizing (with his wife Chana) the world’s first symposium/conference dealing with the subject of cryonics and dementia. It is all the more impressive because Aschwin is a man in his 30s.

The symposium required no registration, registration fee, or notification of attendance. One man attended because another attendee had informed his wife of the event while on an airplane to Portland. There were only about 30 people at the event, but the quality of the attendees and presenters was very high. The event was held at Kaos Softwear, a manufacturing company where Chana is a manager. All the talks were allotted one full hour.

Chana, who has a master’s degree in neuroscience, was the first presenter. Her topic was neurogenesis — the creation of new neurons. Although neurogenesis was discovered in 1965, because neurons are post-mitotic (are non-dividing cells), the discovery was viewed with skepticism until the discovery of neural stem cells in 1992. Neurogenesis only occurs in two discrete areas of the mammalian brain: in the olfactory system and in the hippocampus. The latter is more crucial, although the exclusion of the cerebral cortex is of great concern insofar as that is the probable location of memory, identity, and decision-making. The hippocampus prepares new memories for long-term storage in the cerebral cortex. Chana asked lots of questions for which there are yet no answers. Why does the hippocampus need to create new neurons in the creation of new memories? How is neurogenesis used? How is neurogenesis regulated? Neurogenesis declines with age, and is enhanced with exercise or ischemia. Ultimately, endogenous neurogenesis does not appear to hold much promise as a repair strategy for AD or other forms of dementia. However, it is a worthwhile endeavor to understand neurogenesis in order to guide our own attempts at neuronal repair and/or replacement.

Aubrey de Grey began his talk by acknowledging that none of the work being funded in the 2012 $4.5 million budget of his SENS (Strategies for Engineered Negligible Senescence) Foundation is focused on repairing the brain, although there is a project determining the rate of accumulation of epimutations, that is not focused on repair. He spent the first half-hour reviewing the SENS program, and the next 15 minutes explaining why 3 of the 7 SENS strategies are particularly applicable to dementia: (1) Neurofibrillary tangles and soluble amyloid in Alzheimer’s disease (AD), and their counterparts in other neurodegenerative diseases, are intracellular junk, (2) amyloid plaque in AD is extracellular junk, and (3) late-stage neurodegeneration involves cell loss. Dr. de Grey said that intracellular junk shows signs of failed autophagy. He said that most of the intracellular junk in dementia is protein. It should be easier to dispose of than the cholesterol degradation products which are the focus of SENS lysosome work on atherosclerosis, but which are not properly delivered to the lysosome. He outlined the circumstantial evidence that the main problem may be the same as in atherosclerosis, i.e. oxidized cholesterol poisoning the lysosome. He spoke of the current clinical trials for having microglia eliminate extracellular junk (amyloid plaques). The first human clinical trials had shown great promise, but were halted because 5% of the patients developed brain inflammations. The newer trials have apparently corrected that problem. Aubrey noted the widespread belief that the amyloid would be removed without being of much benefit – expressing his belief that this misses the point, because major postponement or reversal of AD will require fixing all three main problems, hence lack of benefit from fixing one is not evidence that that one need not be fixed. I am one of the skeptics because follow-up autopsies on the first trials showed that even when amyloid plaques had been completely removed, no reduction in degeneration had occurred [THE LANCET; Holmes,C; 372:216 (2008)]. By the time AD is diagnosed, neurodegeneration is too far along to be helped by removing amyloid (though there is rapid progress in improving very early diagnosis). Immunization to remove amyloid would be more effective if begun in the 20s or 30s, much like shots for measles or polio — as prevention rather than cure. Although amyloid may serve a positive function in repair or it would not have evolved. [Aubrey notes: who says it evolved? "Aging is a product of evolutionary neglect, not evolutionary intent" (Hayflick)]. Concerning cell loss, Aubrey was sanguine about Jean Hebert’s work exploiting the fact that certain neural progenitor cells are highly migratory, potentially facilitating widespread distribution of new neurons throughout the neocortex via stem cell therapies. Even if neurons can be replaced in the neocortex, I wonder how that would compensate for the loss of synaptic connections and strength of synaptic connections. Of the three approaches mentioned by Dr. de Grey, I would say that removal of intracellular junk has the best chance of being of benefit on its own, because it is the neurofibrillary tangles that tend to cause cell death rather than the amyloid plaques, which are an upstream event.

My talk was basically a summary of the “Alzheimer’s Disease: Molecular Mechanisms” page in the life extension section of my website BENBEST.COM. I wrote the page in 2003 between leaving my job as bond database support for Scotiabank in Toronto, Canada, and becoming president of the Cryonics Institute in Michigan. For the subsequent 9 years I have become increasingly displeased about how out-dated the webpage was becoming. So I was pleased at the opportunity to do the massive research required to update that webpage for this symposium. Unfortunately, it was all I could do to finish the updating before catching my flight to Portland. Aschwin and Chana allowed me to crash at their condominium. I missed the Friday evening social for those attending the symposium because I spent all evening and a couple of hours the next morning creating my PowerPoint. I was pleased with the result, however, and pleased with the presentation I was able to deliver.

I encourage anyone interested in the content of my talk to consult my Alzheimer’s webpage because that page has detailed linkable references which I could not include in my presentation. I believe that the most promising therapy is the targeting of copper with PBT2, which removes copper from amyloid without chelating essential element metals. Etanercept, which antagonizes the inflammatory cytokine TNF-alpha has also shown promising results. Possibly also, passive immunization with tau antibodies would be of greater benefit in stopping neurodegeneration than immunological approaches against amyloid. Concerning prevention, exercise, curcumin, pomegranate juice, and folic supplementation have shown good results. Seemingly conflicting results would indicate that ginko biloba can slow cognitive decline in Alzheimer’s patients, but is of no benefit in preventing the disease.

Mike Perry’s topic was Early Detection of Alzheimer’s Disease. On that subject he reported that the CerebroSpinal Fluid (CSF) is low in amyloid beta and high in phosphorylated tau protein. I had put much more detail on this subject into the biomarkers section of my webpage on Alzheimer’s Disease – which I showed to Mike later in the day. In his presentation Mike noted even for people who do not get AD, dementia of some kind is still very probable with aging. He commented that AD is not a terminal illness, which is defined as an illness in which two physicians have certified that the patient probably has no more than six months left to live. No AD patient dies of AD — the cause of death is usually infection (pneumonia, bedsores, urinary tract infection, etc.). I expressed concern that suicide by VSED (Voluntary Stopping of Eating and Drinking, as Mike calls it) by an AD victim could lead to autopsy. Mike denied that this was necessarily the case.  I was told that for anyone who had died by refusing food and water the cause of death would be obvious, and no autopsy would be required, though circumstances and policies will vary. Mike Darwin, however, noted that VSED could be harmful to the brain as cardiac arrest draws near, due to low respiration rates. Aschwin responded that this kind of brain damage is still relatively benign in comparison to the alternative (advanced dementia). James Swayze, who is a paraplegic with cryonics arrangements and was in attendance at this event, has expressed concerns that dehydration causes brain damage. Dehydration may reduce brain functionality, but brain dehydration is a key process in removing water from the brain in the vitrification point of view and is probably a benefit rather than a harm for cryonics purposes.  Alzeimer’s patients nearly always die of infection, and because infection may also occur early in the disease,  Mike Darwin recommended that anti-microbial treatment be refused by an Alzheimer’s victim as a way of hastening cryopreservation. If infection does not occur early in the disease, however, refusing antibiotics may not produce the desired result.

Keegan Macintosh, who recently graduated from a Canadian law school, presented on the subject of Thomas Donaldson’s 1988 lawsuit in California to be cryopreserved before his brain cancer destroyed too much of his brain to make cryonics a worthwhile effort. Keegan criticized the attorneys involved in the appeal for arguing that Donaldson’s right to “premortem cryopreservation” stemmed from a constitutionally-protected right to assisted suicide, rather than the right to pursue a risky, but potentially life-saving procedure. By framing the case this way, the Court was able to avoid having to consider Donaldson’s unique and crucially relevant motive, and thus the possibility of cryonics succeeding, for him or anyone else. Acknowledging, however, that options for assisted suicide could be of use to cryonicists with brain-threatening disorders, Keegan examined developments in American law on the issue, and then turned to Canadian jurisprudence. He pointed out a number of potentially significant differences between the U.S. Supreme Court’s substantive due process analysis in the more recent physician-assisted suicide cases, Washington v. Glucksberg and Vacco v. Quill, and Supreme Court of Canada’s approach to section 7 of Canada’s Charter Rights and Freedoms (right to life, liberty and security of the person) in Rodriguez v British Columbia, and cases since. The government’s position is presumably influenced by a desire to avoid a “slippery-slope” that disvalues human life. Keegan noted that although formerly other countries looked to the American Constitution for guidance, Canada’s constitution is now the world’s most popular role-model. Section 2 of Canada’s Charter of Rights and Freedoms emphasizes “freedom of conscience and religion.”

What would be the effect of someone acting on the belief that pre-mortem cremation is the road to salvation? “Freedom of conscience” implies that secular morality is as important as religious belief and there is some emerging jurisprudence to that effect. Would the belief that good-quality cryopreservation is necessary to live again at some future time not then receive equal protection to analogous beliefs and practices of religious origin? Keegan believes that an appeal such as Donaldson’s – and indeed any constitutional challenge against a law impeding access to cryonics – would have a better chance of success in Canada than in the United States.

Max More spoke without slides on the subject of “Survival, Identity, and Extended Mind.” The objective of Max’s talk was to consider how it could be possible to back-up personal identity-relevant information and then reintegrate that information to restore personality if cryopreservation has been imperfect. If cognitive processes and their inputs can be external to the brain, Max would like to take advantage of this to improve the chances of reviving people suffering from brain-threatening disorders. Andy Clark and David Chalmers wrote an authoritative paper entitled “The Extended Mind.” According to Max, for an outside object or process to be considered part of the mind, it has to produce results that are reasonably comparable to the components normally seen internally and biologically/neurologically. Clark and Chalmers propose three conditions for considering externally-located processes to be part of an individual’s cognitive processes: 1) constancy (the external component has to be there reliably); 2) accessibility (a natural ease of use of that component); and 3) automatic endorsement (the person must trust the component as they would trust any comparable part of their natural body). Max noted that a few years before the Clark/Chalmers paper he had considered the related issue of when an external technology could be considered part of the self (in chapter 4 of his dissertation: “Technological Transformation and Assimilation”). Although Max doubted Ray Kurzweil’s claim that an externally-convincing simulation of his father (made out of traces available) would actually have a self, Max did not argue that no well-simulated person could have a self. Max suggested that a notebook could be part of the thinking process, rather than just a tool. Nonetheless, he was dubious about the value of keeping lots of diaries, although it has been suggested that biographical information could assist in reconstruction of a cryonics patient and that cryonics organizations should take a more proactive role in fasciliting storage of identity- and memory relevant information. Max was also dubious that a computer that could convincingly simulate a person would have a self. He raised the question “What is self?” He referred to David Hume’s claim to introspectively only be able to discover thoughts and feelings, but no self. Dennett called self an illusion. This would lead me to believe that neither Hume nor Dennett should have much concern with their own survival (like most people?). Max said that he could lose a few memories without feeling his self was compromised — because he believes that personal identity is more than memory. It includes dispositions, values, and so on.

After the presentations there was a panel of all the presenters, plus Aschwin the host. I requested that each panelist explain what they would do if diagnosed with AD. Aschwin said he would immediately proceed to terminate his life under conditions favorable to cryopreservation provided that the diagnosis was credible and there are no short-term cures on the horizon. Keegan said that he would see first what, if any, time he had before symptoms such as apathy and denial would be expected to set in, and take some conservative portion of that time remaining to spend some quality time with family and friends. Keegan noted that, despite our best efforts, cryonics may not work, and thus it is rational to seek meaningful experiences in the moments one knows they have left, if such can be done without irreparably compromising one’s cryopreservation. I noted that Robert Ettinger also said he would terminate life by hypothermia in a cold bathtub at the end of a party with friends – but delayed such an action to the point where he lost consciousness and lost the ability to do any such thing at the age of 92 when he deanimated. I said that I would probably spend about a year attempting to confirm the diagnosis, and might delay further trying to determine if a cure was possible or forthcoming soon. Max said that he would want a second opinion, but like Keegan wanted to have some joyful time before self-termination. Chana said that she would be very concerned about how the decision to self-terminate would affect others, in particular how to explain to her family why she was ending her life while outwardly being in good health. Chana and Aschwin spoke of being sensitive to each other’s feelings about the matter. Aschwin noted that those who care for AD family members to a natural death often suffer from severe caregiver depression. Chana said that once she had decided to pull the plug that she would “find a way to take a bath in Agent Orange and take advantage of Oregon laws.” By this she meant she would find a way to give herself an aggressive form of cancer that would cause two Oregon physicians to declare that she is a terminal patient. Once this is done, an Oregon physician can write a prescription for phenobarbital which the patient can use for suicide by overdose at the time and place of their choosing. Aubrey said that he would delay the decision without worrying too much about loss of neurons. In addition to delaying because of diagnosis confirmation and evaluating hope for a cure within a short time period, Aubrey added evaluating the likelihood that cryopreservation procedures would be improved by waiting. Mike Perry said that he would try to confirm the diagnosis and if sure about it, “get it [deanimation] over with as soon as possible.”

I mentioned the case of a CI Member dying of cancer who, with her husband, called Suspended Animation, Inc., to be present at their suicide. Her 30-year-old husband was in good health, but did not want to live without his wife and planned to die along with her. CI terminated both their memberships and established a policy of reserving the right to cancel cryonics contracts in cases of suicide. Aschwin strongly disapproved of this CI policy. In his opinion, cryonics organizations should never encourage or condone suicide but should not refuse cryopreservation to those who have taken their own lives. I believe cryonics organizations cannot be seen as encouraging the hastening of death on the ground that cryonics may work, and must ensure that others do not get that impression. Not enough was said about what policies would be most appropriate for cryonics organizations.

I asked Aubrey if he thought that an AD patient would ever be so advanced that SENS could not save the self. Aubrey agreed that could happen, but it would be difficult to say when. The case is similar with straight frozen patients or patients with varying amounts of ischemic damage. The concept of “information theoretic death” is meaningful, but difficult to determine. Even if SENS methods could not recover enough memory and identity to save a person, some future molecular archeology might be able to do so.

There was some discussion about the most promising treatments for Alzheimer’s disease. Aschwin pointed out that both early-onset Alzheimer’s and late onset Alzheimer’s have a strong genetic component, which should favor the use of gene therapy.

Mike described the activities of the Venturists, which is offering to save Venturist Members who are being cryopreserved by a cryonics organization that fails. Another project of the Venturists is that they are seeking $50,000 for Mike Darwin, who lost his cryopreservation arrangements with Alcor due to financial difficulties.