Keeping Cryonics Affordable

What can be done to keep cryonics affordable? Or perhaps one should say; what can be done to maintain your cryonics arrangements until the time you will need them?

Let’s start by asking the question whether cryonics is an expensive procedure. One might argue that cryonics is comparable to other advanced medical procedures such as bypass surgery or brain tumor removal, and a lot less expensive than the (futile) end-of- life care costs that are incurred by many individuals late in life. The monthly costs of life insurance and membership dues are lower than the typical health insurance premium. Unfortunately, one thing that sets cryonics apart from many of these examples is that it requires an active, ongoing, effort to maintain this affordability and neglect (not paying one’s life insurance premiums) can render all of one’s efforts in vain. As affordable as the monthly costs of cryonics may be for many people, most of us do not have the resources to fork over the total cryopreservation minimums (either neuro or whole body) without utilizing insurance or a well-designed estate plan.

The first step is to take out life insurance that is at least appropriate for the cryopreservation arrangements of one’s choice. This has been emphasized before but cannot be reiterated enough. When you are young and healthy, life insurance premiums are much lower. Even if you are not sure whether to make cryonics arrangements yet, having a life insurance policy in place can give you that peace of mind and allow you to secure lower premiums. If income permits, you can take out more insurance than is needed to cover your cryopreservation minimums so that future cost increases can be accommodated. With “premium funding” of at least $20,000 above your minimum, Alcor waives the annual $180 Comprehensive Standby Fee (the “CMS Waiver”).

In my experience many cryonics members spent little time reviewing their existing life insurance policies after they put them in place. This is not a prudent approach, especially for members whose life insurance policies were just sufficient to cover their cryopreservation minimums at the time of joining. If your income increases and this looks like a relatively dependable feature of your future, it can make good sense to increase the coverage of your life insurance policy. This is especially a smart thing to do for members who are still relatively young but further along in their careers.

Another important step is to keep your cryonics arrangements in place throughout your life. Alcor is increasingly moving towards a loyalty-based dues system in which one’s dues diminish over time, for those whose membership in good standing is uninterrupted. One advantage of this decreasing dues system is that your dues will go down when you reach a point in your life when you may no longer work.

What can Alcor do to keep cryonics affordable for you? From the administrative side it can “nudge” you to ensure you do not fall behind on dues (automatic deductions) and remind you to upgrade insufficient or poorly-performing insurance policies. It should aim to take advantage of economies of scale by automating administrative and technical functions and use unexpected surplus income to reduce costs in the long run. Eventually there may come a point where the patient number is high enough to create storage solutions that substantially reduce liquid nitrogen boil-off.

The most important step that Alcor can take now to reduce costs and increase the quality of care is to merge the remote standby/stabilization phase of its procedures with its cryoprotection phase. This “field cryoprotection” is already our recommended protocol for overseas cases. If it can be implemented in many major areas in the US, significant cost reductions may be possible. It is not often that a cryonics organization can improve its procedures and save money at the same time.

Originally published as a column (Quod incepimus conficiemus) in Cryonics magazine, September -October, 2017

Premedication in Cryonics Revisited

Disclaimer: Alcor cannot provide medical care for living patients and must regard the care and medication of legally living members as the sole responsibility of members and their treating physicians. To avoid conflict of interest Alcor cannot advocate premedication protocols for cryonics patients.

If there are medications, nutrients, minerals, and/ or vitamins that can mitigate the adverse effects of ischemia after circulatory arrest, it stands to reason that some of these strategies may even confer greater benefits if they are already being pursued prior to pronouncement of legal death.

Two surveys of the topic of premedication, the only such writings that I know of, were penned by Michael Darwin many years ago. The first is “Reducing Ischemic Damage in Cryonic Suspension Patients by Premedication” (Cryonics, April 1991). The second, more extensive treatment is “Premedication of the Human Cryopreservation Patient,” Chapter 7 of the 1994 cryonics manual Standby: End-Stage Care of the Human Cryopreservation Patient. One case report showing use of premedication is that of James Gallagher, 1995 (Alcor Patient A-1871).

In his contributions, Darwin covers topics such as medico-legal issues, risks and benefits, patient evaluation, drug categories, specific medications, evidence, contraindications, etc. Here I briefly review some recent stabilization medications research for its relevance to premedication protocols.

Broadly speaking, there are two categories of premedication drugs: (1) Drugs aimed at preventing certain events following circulatory arrest and (2) drugs aimed at mitigating the damage that (inevitably) follows circulatory arrest. An example of the former is prevention of blood clots and an example of the latter is ischemia-induced free radical generation.

When our lab, Advanced Neural Biosciences, conducted stabilization medications research we administered medications prior to or concurrent with circulatory arrest. This model is effective in
looking at the efficacy of drugs but in real human cryopreservation administration of medications is often delayed. An interesting feature of this model, however, is that it may tell us something about the efficacy of these medications had they been part of a premedication regime.

As reported in our research summary in the January-February, 2017 issue of Cryonics magazine, we only found consistent and beneficial effects for two medications; heparin and sodium citrate. Both agents prevent the formation of blood clots, although sodium citrate may also exhibit general neuroprotective properties as a calcium chelator.

If we reflect on these results with the two categories of drugs discussed above in mind, it is tempting to conclude that only drugs that can prevent a specific ischemia-induced effect (like blood clotting) can improve the cryopreservation of the patient. This would be premature to conclude at this stage. Not just because of our choice of animal model and sample size, but because some of the medications in Alcor’s stabilization protocol may better help to sustain biological viability after the start of cryonics procedures and/or inhibit biochemical events that degrade brain ultrastructure.

Stabilization medications research can provide data to formulate an evidence-based premedication program, but there are issues that are unique to premedication. For example, a highly effective agent like sodium citrate cannot be administered prior pronouncement of legal death because it immediately stops the heart. There are also medications that may be effective for the critically ill patient (for example, drugs aimed at preventing arrhythmias and sudden death during decline) that have no meaningful role to play in cryonics stabilization procedures.

Originally published as a column (Quod incepimus conficiemus) in Cryonics magazine, May-June, 2017

The False Hope of Cryonics

One of the most common accusations leveled at cryonics organizations is that they offer “false hope.” For this accusation to make sense, critics would have to demonstrate it is impossible in principle, or at least highly unlikely, for cryonics to work.

What would it mean for cryonics organizations to offer a service which, at best, is “highly unlikely to work”? If the cryonics premise, that cryogenically preserved individuals could eventually be revived in a functioning, healthy state with memories reasonably intact, contradicted the known (or well-accepted) laws of physics, one could certainly justify the charge of “false hope.” But who has ever shown this? No one, of course. Nor have they approximated it by arguing that “well, it probably contradicts what is physically possible, including any technology likely to ever be developed in the future.” Has anyone shown this? (Have you seen any of their probability estimates and do you agree with them?) For cryonics to have the best chance of working, deterioration of the body needs to be halted as soon as possible and future medical technologies will need to cure the original disease of the patient – and any additional damage sustained during the cryopreservation process itself. It is commonly assumed that some kind of medical technology will be needed that can manipulate matter at the molecular level. Such developments are envisioned and being developed right now. Human biology itself demonstrates on a daily basis that it is possible to conduct biochemical actions with molecular precision.

A more empirical, biological, argument that could be made is that deterioration of the brain after pronouncement of legal death is so rapid that there is not enough left of the brain to repair or even infer its original state. It can be admitted that resuscitation without cognitive deficits is challenging or presently impossible after circulatory arrest of 10 minutes or more. But this does not mean that the ultrastructure of the brain itself has been wiped out. In fact, experimental studies that actually look at this ultrastructure do not show major changes to identity-critical structures for hours after cardiac arrest.

Critics also tend to conflate their criticism of cryonics done under good conditions with what is done under difficult, suboptimal circumstances, as if the obviously bad scenarios could not be improved upon even under the best of circumstances. Current cryonics protocol at Alcor is to start cryonics procedures (restoring circulation, cooling) immediately after pronouncement of legal death. (If cryonics were recognized as an elective medical procedure, there would be an even smoother transition, with less stress to the tissues, from terminal illness to cryopreservation.)

What about freezing damage? If a human brain is frozen without cryoprotection the freezing damage will be considerable. But does this damage preclude inferring the undamaged state of the brain from the damaged state? I am not aware of any serious arguments or empirical studies that show this. One important point that always needs to be kept in mind about cryonics is that damage occurs at the same time as molecular motion is arrested by cold, and cold is not a reliable means of erasing information. But more importantly, the freezing-damage argument is misplaced because in cryonics the brain is vitrified instead of frozen, which largely eliminates freezing damage. True, the high concentrations of cryoprotectants needed for vitrification still cause some degree of toxicity. But this kind of injury is not the mechanical damage seen in freezing, and may even be difficult to detect on an ultrastructural level at all.

As far as I can tell, the naïve and irresponsible accusation that cryonics offers a “false hope” rests on either a misunderstanding about what is involved in cryonics (or would be needed for success) or what cryonics organizations communicate to (prospective) members.  Considering the trends toward reversible cryopreservation and further miniaturization in engineering and medicine, it is reasonable to expect that the conditions for cryonics to work will be met in the future. Cryonics is not just an “act of faith” but an “act of reason.”

I would even go further and claim that those who uncritically throw around phrases like “false hope” are encouraging a form of “false despair.” For they categorically refuse to engage with the logical arguments and science that support cryonics. Their reckless talk instead is a further supporting buttress for  rationalizations of aging, disease, and death. All this we firmly reject, and instead are working toward further human enhancement.

Originally submitted as a column (Quod incepimus conficiemus) for Cryonics magazine, March-April, 2017. Readers may want to compare with the alternative exposition by Ralph Merkle the magazine published.

Alcor Associate Membership

As of writing, Alcor has more than 1100 members with cryonics arrangements. The Alcor Facebook page, however, has more than 14,000 likes. While it is easy to “like” something on social media, this number indicates that there are a lot of people who support our mission and research but are not quite ready to make cryonics arrangements for themselves. In 2012, I sent a proposal to the Alcor Advisors and Board of Directors to introduce a new kind of membership that allows people who support Alcor’s mission to join the organization as Associate Members. Associate Members pay a small annual fee ($60 or $5 a month) and get a paper copy of Alcor’s magazine, discounts on conferences and events, access to the Alcor forum, and the paid fees can be used to lower or eliminate the application fee for full membership. Alcor now has 317 Associate Members. This is not bad at all, but membership statistics at other cryonics organizations, such as the Cryonics Institute, indicate that it should be possible to have at least twice the amount of Associate Members as members with full cryonics arrangements.

One attractive feature of Associate Membership is that, unlike full membership, it can be easily gifted to friends and family, too. In fact, what I would like to achieve with this column is to encourage each and every reader (yes, you, too!) to think of someone who supports cryonics and life extension and encourage them to become an Associate Member, or even gift it to them.

You know this friend who is still figuring out her life insurance…Associate Membership!

What about that person who would like to join Alcor in the future but only when they introduce fracture free storage… Associate Membership!

That colleague who is fascinated with the idea of cryonics needs to think about it a little more…Associate Membership.

And there is this person who has been saying for 5 years now that they will sign up but never gets around to start the process…. Associate Membership.

Not sure about which cryonics organization to join? Join both major US cryonics organizations as a non-funded member and learn more.

What would it be like if Alcor had 5,000 Associate Members instead of 300? For starters, more resources would be available for publication of the magazine, social media presence, bigger conferences, and other outreach events. Local life extension and cryonics groups would see substantial growth in attendance, and new groups can be started to bring people with shared interests together. Support for cryonics research would grow. And when cryonics is under threat by hostile critics or legislators, we can draw from more people to mount an effective response. And perhaps, most importantly, a larger membership will allow Alcor to recruit more (young) talented writers, advocates, and researchers who can work together to bring human suspended animation closer to reality and strengthen the scientific and legal status of human cryopreservation.

So think hard about all these conversations you had over the last couple of years, or the people you’d really, really, like to see reading more about cryonics and Alcor and call Alcor (480) 905-1906 or head over here, and give the gift of life:

http://www.alcor.org/BecomeMember/ associate.html

Originally published as a column (Quod incepimus conficiemus) in Cryonics magazine, January-February, 2017

Advances in Cryoprotectant Toxicity Research

There is little disagreement among cryobiologists that the biggest limiting factor to reversible organ cryopreservation is cryoprotectant toxicity. It is actually not that hard to create vitrification solutions that completely inhibit ice formation at even the slowest cooling rates. The problem is that such highly concentrated vitrification solutions are too toxic to permit recovery of complex organs. The least toxic vitrification solution for complex mammalian organs as of writing is M22. M22 is the culmination of many years of experimental and theoretical work by cryobiologist Greg Fahy and colleagues.

Studying cryoprotectant mixtures on rabbit kidney slices, Fahy and colleagues came to the following conclusions:

1. High concentrations of a cryoprotective agent (or a mixture of different cryoprotective agents)
can prevent ice formation during cooldown and warming.

2. The toxicity of some cryoprotectants can be neutralized by combining them with other cryoprotectants.

3. The non-specific toxicity of a cryoprotectant solution can be predicted by calculating a quantity (“qv*”) which is intended to measure the average hydrogen-bonding strength of the cryoprotectant polar groups with the water molecules in the solution.

4. Within limits, non-penetrating agents can reduce the exposure of cells to toxic amounts of cryoprotectants without reducing vitrification ability.

5. Synthetic “ice blockers” can be included in a vitrification mixture to reduce the concentration of toxic cryoprotective agents necessary to achieve vitrification.

While M22 is a low toxicity solution, its toxicity profile still necessitates minimizing exposure time and introduction and removal at low (subzero) temperatures. If we had a better understanding of the mechanisms of cryoprotectant toxicity, vitrification solutions with no toxicity at all could be introduced at higher temperatures and exposure times could be increased to optimize complete equilibration of the tissue with the cryoprotectant.

Two major reviews of cryoprotectant toxicity were published in the last 5 years; Gregory Fahy’s“Cryoprotectant Toxicity Neutralization” (Cryobiology, 2010) and Benjamin Best’s “Cryoprotective Toxicity: Facts, Issues, and Questions” (Rejuvenation Research, 2015).

Greg Fahy’s paper is a rigorous exposition of experimental results concerning the phenomenon of cryoprotectant toxicity neutralization. The paper is mostly limited to the discovery that DMSO can block the toxic effects of amides such as formamide. The combination of DMSO and formamide (or other amides such as urea and acetamide) is indeed one of the building blocks of M22 but this combination cannot be used without limit and the paper includes data that indicate the maximum molar concentrations (and ratios) that still permit full viability. In theory, if two (or more) cryoprotectants would completely neutralize each other’s toxicity they could be the sole components of a vitrification solution. But as the formulation of M22 shows, it is still necessary to add weak glass formers such as ethylene glycol, extracellular CPA’s, and “ice blockers” to supplement the toxicity neutralization obtained with formamide and DMSO. An important finding in Fahy’s paper is that n-methylation abolishes toxicity neutralization for amides and combining methylated amides also does not lead to toxicity neutralization between
them. In fact, Fahy found that the presence of n-methylated compounds renders even small amounts of DMSO toxic. The remainder of the paper discusses the mechanisms of cryoprotectant toxicity and Fahy now favors protein denaturation as a plausible mechanism of (non-specific) toxicity. While other cases of toxicity neutralization have been reported in the literature, no rigorous studies have been done to produce a body of knowledge that is comparable to what we know about amide-DMSO interactions.

Benjamin Best’s paper is more general in scope but discusses a lot of experimental data from other papers and also critically discusses Fahy’s work on cryoprotectant toxicity. As Ben Best points out, different (and seemingly contradictory) results do not necessarily mean that cryoprotectant toxicity is a species or cell-type dependent phenomenon. One could imagine a meta-analysis of cryobiology data in which variables such as concentration, loading and unloading protocols, exposure temperature, exposure time, and the type of viability assay are matched to ensure methodological consistency. It is also important to compare cryoprotectants at their minimum concentration to vitrify to make meaningful toxicity comparisons.

If the work at 21st Century Medicine is an indication, universal low-toxicity cryoprotective solutions should be feasible. Perhaps the most interesting part of the paper is where Best offers a critique of Greg Fahy’s “qv* hypothesis of cryoprotectant toxicity,” which aims to show that non-specfic toxicity concerns the degree to which cryoprotectants leave water available to hydrate macromolecules. This discovery allowed for the substitution of ethylene glycol for propylene glycol in Fahy’s lower toxicity vitrification solutions, despite the resulting higher CPA concentrations. Best observes, “it seems contradictory that water remains available for hydration, but not available for ice formation.” A potential rejoinder to this observation is that so called “bound water” does not participate in ice formation but can be disturbed by strong glass formers. Best also suggests a potential refinement of qv* that allows for more precise calculation of the hydrogen bonding strength of the polar groups that are used to calculate qv*. It is conceivable that such a refinement would eliminate the few remaining outliers in the data that support the qv* hypothesis. The paper also draws attention to the possibility of kosmotropic co-solvents and changes of pH and microenvironment polarity to mitigate cryoprotectant toxicity.

Neither of the papers discusses cryopreservation of the mammalian brain, but there is good reason to believe that in the case of this organ, modification of low-toxicity vitrification solutions is required. Conventional cryoprotective agents such as PG, EG, and DMSO have poor blood brain barrier (BBB) penetration and the brain may not tolerate the CPA exposure times that other organs do. For example, while M22 can be used for cryopreservation of the brain, many of its component have poor BBB penetration and PVP and the ice blockers (X-1000 and Z-1000) are assumed not to cross the (non-ischemic) BBB at all. One potential solution is to (reversibly) open the BBB with so-called BBB modifying agents like detergents or perhaps to search for cryoprotective agents that can cross the BBB.

The most fundamental question in the design of vitrification solutions remains whether it is possible at all to introduce high concentrations of cryoprotectants without creating any kind of irreversible molecular and ultrastructural adverse effects. Understanding what specific and nonspecific cryoprotectant toxicity exactly is should enable us to answer this question.

Originally published as a column (Quod incepimus conficiemus) in Cryonics magazine, August-September, 2016

Scientific Proof for Cryonics?

A cryonics advocate makes an eloquent case for cryonics. Then a scientist is called upon to dismiss the idea of cryonics because there is “no proof” for it. Unfortunately, such a statement reveals that the “scientist” in question does not know the difference between empirical science and logic, and also does not understand the difference between cryonics and suspended animation.

As the evolutionary biologist Satoshi Kanazawa writes in a November 16, 2008 column for Psychology Today “The knowledge that there is no such thing as a scientific proof should give you a very easy way to tell real scientists from hacks and wannabes… Proofs exist only in mathematics and logic, not in science. Mathematics and logic are both closed, self-contained systems of propositions, whereas science is empirical and deals with nature as it exists. The primary criterion and standard of evaluation of scientific theory is evidence, not proof.” He goes on to write that “all scientific knowledge is tentative and provisional, and nothing is final. There is no such thing as final proven knowledge in science.”

What is the proper role of science in cryonics? Let’s say that a person proposes that if we freeze a person after clinical death there is a reasonable expectation that more advanced medical technologies can reverse the freezing damage, the medical condition that gave rise to this person’s critical condition, and also the aging process that caused this medical condition in the first place. We can respond to this proposal by asking a number of questions. What will freezing do to the fine structure of the brain? How will future medical technologies infer the original state of the brain from the frozen state? What kind of technologies are required to repair the brain and restore the person to a healthy and youthful state?

These are the kinds of questions where science (and reasonable extrapolations of where science will be heading) is important in evaluating the idea of cryonics. And we are not limited to just consulting existing science, we can also push science in the direction of minimizing the damage incurred during cryopreservation so the odds of revival for the typical cryonics patient will increase. For example, in 2000 Alcor changed its protocol from limiting freezing to eliminating it through a technology called vitrification. Advances in gene editing, virus modification, and nano-scale 3D printing can make the idea of cell repair more plausible. Advances in science and technology of this nature can make people update their prior (subjective) estimates about the probability of cryonics being successful.

What such advances in science cannot do is to provide “proof ” that cryonics will work. They cannot do this because all scientific knowledge is “tentative and provisional,” but it also cannot do this for a more fundamental reason. Cryonics is not suspended animation. Cryonics concerns
stabilizing people for whom no successful medical treatment is available to permit them to benefit from future advances in medicine. By definition, it is not possible to prove that these technologies will become available.

What people who insist on “proof ” for cryonics want to see is evidence of reversible cryopreservation. Human suspended animation is indeed a research- and clinical objective that a credible cryonics organization should aim for. But it cannot be emphasized enough that while “proof ” of suspended animation would provide strong support for the practice of cryonics is it is not necessary for the cryonics idea to be plausible. What is necessary for cryonics to work is that the brain (and rest of the body) of a person are preserved to a degree that the original, healthy, state of the brain can be inferred from the preserved state. Perhaps future “neurological archeology” technologies will reveal that even freezing of the brain without cryoprotectant allows for complete revival.

A proper understanding of cryonics requires that scientists recognize the difference between providing proof and updating expectations based on empirical evidence. But it also requires the scientist, as the great cryonics writer Thomas Donaldson once recognized, to make peace with the unknown because the capabilities of future science remain a matter of debate and we cannot say for certain when a person is dead by information-theoretic criteria.

Originally published as a column (Quod incepimus conficiemus) in Cryonics magazine, July-August, 2016

How “Repair Denialism” Prevents a Rational Discussion About Cryonics

Scientific critics of cryonics often do not seem to understand the basics of cryobiology (freezing does not “burst” cells), or remain ignorant that cryopreservation without freezing (“vitrification”) has been a routine procedure in cryonics since 2000. It is not surprising, then, that some advocates of cryonics question the integrity of such critics. Are they deliberately ignoring or distorting the evidence that supports the technical feasibility of cryonics?

One Alcor official has informally called such critics “cryonics deniers.” One might object to using such a strong characterization because the feasibility of cryonics is a conjecture, not a fact. I would like to suggest a more specific kind of denial. Many critics of cryonics seem unwilling to recognize the possibility of repair, or at least not factor it in when evaluating the coherence of arguments in favor of cryonics.

The ultimate goal of cryonics organizations is to offer reversible human cryopreservation (suspended animation) but is proof of suspended animation necessary for cryonics to be plausible?

The answer to this question is a resounding ‘NO.” To reiterate the premise of cryonics; long term care at cryogenic temperatures allows the person to take advantage of medical advances of the future, including cell repair. Cryonics permits the use of an imperfect preservation technique, provided that the damage produced by sub-optimal technologies does not exclude inferring the original state of the brain (or body) from the damaged state. This is a subtle, but important implication of the idea of medical time travel. Pointing out that existing cryopreservation techniques are imperfect does not refute the cryonics premise, unless it can be shown that such techniques produce information-theoretic death.

Not all injuries to the brain can be repaired. For example, when the period of cerebral ischemia is so extensive that bacteria-driven putrefaction has erased most of the brain structure, meaningful restoration is not likely to be possible. Do all sub-optimal cryopreservation technologies that fall short of true suspended animation produce this kind of damage? Not likely! For example, let’s assume that modern vitrification solutions produce some degree of protein denaturation and membrane damage that compromise viability. Is it plausible to argue that this completely renders the idea of repair impossible? Does ice formation produce alterations in the brain that do not allow future “reconstructive connectomics” techniques to infer the non-frozen state from the frozen state? Sweeping claims about “freezing damage” are not acceptable substitutes for detailed structural arguments, especially given the fact that damage incurred during the cryopreservation process is also locked into place by those same low temperatures.

One might object that the idea of cell repair is itself implausible, i.e. that the laws of physics do not permit the idea of healing at the molecular level. The problem with this argument is that human biology already features molecular assembly and DNA repair. Whether one subscribes to the idea of mechanical molecular nanotechnology, modification of viruses or white blood cells, or further miniaturization of 3D printing, it is reasonable to assume that some kind of nanomedicine will be developed in the future.

I once called the idea that human suspended animation is a necessary condition for cryonics to be taken seriously the “Prehoda fallacy.” (Robert Prehoda in the 1960s was an early champion of this position.) It does not serve advocates of cryonics well to discuss the feasibility of cryonics without discussing the plausibility of molecular medicine. If a critic of cryonics claims that cryonics is not technically feasible, insist upon a detailed exposition why the forms of damage associated with today’s technologies cannot be repaired by future medical technologies.

Originally published as a column (Quod incepimus conficiemus) in Cryonics magazine, May-June, 2016

Human Biostasis Options: Advantages and Limitations

On February 9, 2016 the Brain Preservation Foundation announced that the cryobiology company 21st Century Medicine had won their small mammal brain preservation prize. The team at 21st Century Medicine used a procedure named Aldehyde-Stabilized Cryopreservation (ASC) to preserve the ultrastructure of the brain in a “near-perfect” condition. It is important to understand how ASC differs from both conventional cryopreservation and other human biostasis alternatives to understand its merits and limitations.

In conventional cryopreservation (which is the procedure Alcor currently uses) the blood (and cell water) in the brain is replaced with a vitrification agent that permits long term storage at liquid nitrogen temperature without further degradation. The advantage of this method is that it seeks to both preserve viability and the fine ultrastructure of the brain. Currently, the disadvantage of this method is that it produces (severe) cerebral and cellular dehydration, which alters the ultrastructure of the brain and renders some components of the brain difficult to observe in electron micrographs.

A radically different alternative to cryopreservation is to chemically fix the brain with aldehydes (formaldehyde, glutaraldehyde) and store the brain at room temperature or in a fridge in the liquid state. While some people consider such a procedure “better than nothing”, Alcor does not support this kind of “chemopreservation” as a long term care option due to concerns about long-term degradation and  sub-optimal preservation in ischemic cases. An extensive critique of liquid state chemopreservation can be found in my article ‘Chemical Brain Preservation and Human Suspended Animation.’

What is notable about the procedure that won the small mammal brain preservation prize is that it combines both aldehyde fixation and vitrification. In short, first the brain is perfused with glutaraldehyde, followed by perfusion of a high concentration of cryoprotectant to protect the brain against ice formation during long term care. This idea is actually not new and was discussed in in the mid-1980s in Eric Drexler’s book Engines of Creation. The renewed popularity
and technological development of this idea was recently triggered by the formation of the Brain Preservation Foundation and its emphasis on ultrastructural preservation. The protocol that won the small mammal brain cryopreservation prize has shown indeed a degree of ultrastructural preservation that has not yet been achieved with conventional brain cryopreservation.

Alcor’s biggest concern with aldehyde-stabilized cryopreservation is that it renders the tissue completely dead by contemporary viability criteria by creating irreversible crosslinks between bio-molecules. Despite claims to preserve the “connectome”, at the molecular level structure is fundamentally altered. In terms of research aimed at reversible biopreservation, this is a dead end.

Conventional cryo, conventional chemo, and a combination of the two are the three most discussed options of human biopreservation. Other, hypothetical possibilities include (a) vitrification with agents with much higher glass transition temperatures that permit warmer storage such as at dry ice temperature (b) poly-vitrification, in which high molecular weight polymers are used to stabilize the patient near or at room temperature, and (c) the use of molecular nanobots to induce reversible biostasis (an idea originally proposed by Robert Freitas).

The current position of Alcor is to keep researching and offering conventional cryopreservation without the use of chemical fixatives. The research emphasis of the organization and associated labs this year will be to produce better electron micrographs of cryopreserved brains and the validation of blood brain barrier modifying agents to eliminate the severe dehydration that is currently observed in “good” cryonics cases.

Originally published as a column (Quod incepimus conficiemus) in Cryonics magazine, March-April, 2016

Cryonics Without Cerebral Dehydration?

One of the interesting things about technological progress in cryonics is that awareness of technological problems, and the desire to solve them, is often dependent on other problems being solved first. For example, cryoprotectant toxicity became a more serious concern after it was possible to eliminate ice formation. After all, it is more important to eliminate severe (mechanical) damage caused by ice crystals than to prevent (minor) alterations of biomolecules.
One problem that is increasingly rising to the top of technological issues to be solved is the extreme dehydration caused by the perfusion of cryoprotectants.

The fact that perfusion of the brain with cryoprotectants causes substantial dehydration has been known in cryonics for a long time. While no rigorous academic studies are available about this topic, it is usually assumed that the cause of this dehydration is that most (but not all) cryoprotectants have poor blood brain barrier (BBB) permeability.

Another line of evidence is that prolonged warm and cold ischemia eliminate this dehydration, presumably because ischemia compromises the BBB in a time-dependent manner.  One ironic consequence of this is that in cryonics severe dehydration is often an indicator of good patient care (i.e. minimization or mitigation of ischemia). Maybe because of this there has been relatively little interest in eliminating CPA-induced cerebral dehydration.

Another reason is that dehydration actually assists in removing water from the brain to facilitate vitrification, perhaps even requiring lower concentrations of cryoprotectant than are necessary for the vitrification of other organs (preliminary evidence for this exists).

Cerebral dehydration was identified as a potential form of injury in a case report for patient A-1097 (2006) but until recently the “advantages” of dehydration seemed to outweigh its potential disadvantages. More serious concerns started to emerge in the last couple of years. Electron micrographs of brains cryopreserved with M22 and other cryoprotectants show ultrastructural alterations that are primarily presumed to be due to CPA-induced dehydration. The significance of this issue was further reinforced in 2015 when a researcher from 21st Century Medicine showed electron micrographs of aldehyde-stabilized vitrified brains (vitrification after chemical fixation) that look considerably better than traditionally vitrified brains. In addition, while employed for the Cryonics Institute, Yuri Pichugin demonstrated that the extreme dehydration associated with modern vitrification solutions is not compatible with good brain slice viability.

Since most researchers in cryonics would like to see a biopreservation protocol that does an excellent job of preserving both viability and ultrastructure, eliminating this kind of injury is likely to be a rather important research goal in the next couple of years.

It is not desirable to deliberately induce ischemia to improve BBB permeability of cryoprotectants. This leaves a number of strategies to improve delivery vitrification agents to the brain:

1. Osmotic opening of the BBB. Molecules such as mannitol have a transient effect on BBB permeability but are probably not potent enough  to permit brain cryoprotection without dehydration.

2. Yuri Pichugin has discovered that detergents such as sodium dodecyl sulfate (SDS) permit cryopreservation of the brain without dehydration.

3. Not all cryoprotectants are impermeable to the brain. Can these cryoprotectants be used in
low toxicity vitrification solutions?

Fortunately, the tools to screen the efficacy of BBB modifying technologies for brain cryopreservation are already known in the literature. Brains can be inspected for post-perfusion morphology and weight loss/gain. BBB modifiers can be tested for viability in brain slices or even whole animals. We can compare whether the use of BBB modifying strategies raises or lowers the concentration of cryoprotectant necessary to vitrify the brain. How do BBB modifiers affect overall ultrastructure in electron micrographs? What do BBB modifiers do to other cells and the vasculature? Do BBB modifiers produce more edema in the rest of the body? Will the use of BBB modifiers allow “extracellular” cryoprotectants and ice blockers to cross the BBB or even cells?

One challenge is how to validate and authorize the use of BBB modifying strategies in human cryonics cases. We know from burr hole and CT scans of neuro patients at Alcor that severe cerebral dehydration is frequently seen in good cases with little ischemia (shrinking the brain down to almost 50% of its natural size).

CT scan of Alcor patient with cryoprotectant-induced brain dehydration

Switching to a cryoprotectant that has similar or even lower toxicity as M22 would be relatively straightforward but if potent agents are used to open the BBB it will be important to choose a dosage that does not produce serious side-effects such as fulminating edema or poor cell viability.

In a 2007 Alcor article (“Securing Viability of the Brain in Cryonics”) I speculated that we should assume that viability of the brain (or slices made from such a brain) is currently lost about halfway through cryoprotectant perfusion as consequence of cryoprotectant toxicity. As we understand it now, the need to use high concentrations of cryoprotectants also produces brain shrinking. If we want to move Alcor closer to its mandate of developing reversible human cryopreservation both problems will need to be revolved. This will most likely involve a minor re-formulation of M22 or a novel cryoprotectant that is more “friendly” to the brain.

For 2016, my lab Advanced Neural Biosciences has made identifying such a brain-friendly cryoprotection protocol a high priority. The good news is that we already know of strategies that work. Now we need to identify protocols that maximize high viability and excellent ultrastructure
to make the next step in further closing the gap between cryonics and suspended  animation.

Originally published as a column (Quod incepimus conficiemus) in Cryonics magazine, January-February, 2016

Suspended Animation as a Research Goal and Case Benchmark

Cryonics is a complicated idea to explain and one of the most common misunderstandings is to confuse it with suspended animation. This leads critics to conclude that cryonics cannot work because we are not yet capable of placing a patient in cryostasis and reversing this procedure without causing damage. Advocates of cryonics have written careful expositions to make the point that human suspended animation is a desirable goal but not necessary for cryonics to succeed. I will not go into these arguments here but want to discuss what role the idea of suspended animation can play at Alcor.

First of all, the development of human suspended animation can be a formal research goal of a cryonics organization. As obvious as this may be, I am not aware of any cryonics organization that has communicated that this is their ultimate research objective. This is unfortunate because it is important for our credibility to develop a form of reversible biostasis. After all, if our procedures are fully reversible we do not always need to evoke alternative definitions of death and will often be able to claim that a critically ill patient who is cryopreserved is still alive (without the need for quotation marks around the word death). Offering human suspended animation as a form of biostasis leaves critics to argue that a disease will never be cured as the only remaining objection, which would be a rather preposterous claim.

The goal of offering suspended animation can also guide a cryonics organization to decide which new technologies to introduce and upgrade. For example, suspended animation is incompatible with the presence of fractures (which would need repair) and a transition to cooldown or long term care technologies that prevent fracturing would be a necessary step to move further into the direction of suspended animation. It is important to understand the piecemeal nature of this. A cryonics organization does not go from offering straight freezing to suspended animation overnight but seeks to introduce improved procedures towards that goal on an incremental basis. The more obstacles to suspended animation we can eliminate (ice formation, fracturing), the more identifiable and recognizable the remaining challenges, like cryoprotectant toxicity, will be.

One major misunderstanding about the role of suspended animation is that until we have perfected our technologies, the concept of suspended animation cannot be used as a benchmark to evaluate cases. In fact, we can use the concept of suspended animation in a meaningful way when we write our case reports and discuss case outcomes right now. The reason why we can do this is because loss of viability is not a characteristic of all our procedures but, in a good case, is something that happens further downstream. In an ideal case, we suspect that viability is lost somewhere mid-way during cryoprotective perfusion where the concentration of the cryoprotectant and exposure time render organs non-viable by contemporary viability criteria. Another way of phrasing this is that our procedures should be reversible up to that point. This benchmark is extremely important in evaluating the quality of care at a cryonics organization and guiding procedures in an actual case. It is even possible to identify the point at which viability is lost by monitoring the patient during stabilization procedures and taking a small (microliter) brain or spinal cord biopsy after cryoprotective perfusion.

If Alcor takes itself seriously as a scientific organization, each case report should contain a discussion about how successful the organization was in sustaining viability as long as possible, and if not, whether these problems were beyond Alcor’s control or reflect errors made during the case. This allows us to observe patterns and trends and introduce measures and upgrades that push reversibility further downstream in our procedures.

Originally published as a column (Quod incepimus conficiemus) in Cryonics magazine, December 2015