20. June 2012 · Comments Off · Categories: Cryonics, Death, Neuroscience

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

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

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

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

08. June 2012 · Comments Off · Categories: News

The schedule for the upcoming Portland Cryonics and Brain-Threatening Disorders Symposium has been published.

On July 7, 2012 a number of high-profile and upcoming speakers in the cryonics and life extension community will talk about identity-destroying brain disorders and how diseases like Alzheimer’s can frustrate the objectives of the most ambitious life extentionists. Topics that will be discussed include the pathophysiology of Alzheimer’s, emerging early-diagnosis technologies, neurogenesis in adults, repairing the aging brain, and legal options for people diagnosed with a brain-destroying disease.

Entrance to the symposium is free.

Other activities during this weekend will be announced soon.

The schedule is available here and you can register on our Facebook event page.

09. May 2012 · Comments Off · Categories: News

An additional speaker has been added to the Symposium on Cryonics and Brain-Threatening Disorders line-up.

Keegan Macintosh – Revisiting Donaldson v Van de Kamp: A Comparative Constitutional Analysis

Suffering from a malignant brain tumour, Thomas Donaldson petitioned the California Superior Court in 1990 for a declaration that he had a constitutionally-protected right to “premortem cryopreservation”.  His petition was denied, and his subsequent appeal dismissed.  In this talk, Keegan Macintosh will critically analyze how the case was argued and decided at the appeal level, discuss whether the same or similar arguments would be successful in the US or Canada today, and present novel arguments which would be available under Canada’s Charter of Rights and Freedoms that were and are not available under the US Constitution.
Keegan Macintosh will be receiving his J.D. in May, 2012, and sits on the board of directors of the Cryonics Society of Canada, as well as the Institute for Evidence Based Cryonics.  He is also President of a currently-incorporating life extension non-profit organization in British Columbia, and has been involved in educational outreach efforts in Vancouver on the topics of life extension and cryonics since 2010.

Please register for the event on our Facebook page so we know how many attendees to expect.

This article continues my survey of some of the various forms of legal protection for cryonics patients.  The previous article examined laws that directly affect what happens to a person’s body after legal death, both in the period immediately after declaration of legal death, and indefinitely thereafter.  We saw that the amount of prospective autonomy a person is permitted in this regard can vary significantly from jurisdiction to jurisdiction, with more or less consideration afforded to the wishes of the person’s next of kin, religious beliefs, societal norms and other public interests.  Two other legal structures which can and are used by cryonicists to promote the success and timeliness of cryopreservation, maintenance, and resuscitation are wills and trusts.

As before, this is a broad survey, with references to specific laws for explanatory purposes.  Given the context, it does not go too far to say that for your own safety, you must not rely on the following analysis as legal advice, and should instead consult an advisor licensed to practice in your jurisdiction.

Wills

While a person’s instructions regarding disposition of their human remains may not need to appear in their will in order to be enforceable (in those jurisdictions where such instructions are enforceable), the will’s primary function of distributing the deceased’s property can also be used to promote a cryonics patient’s interest in a timely cryopreservation and revival.

One option that should not be ignored on account of its simplicity, is that a cryonics patient can make gifts through their will to their long-term care provider, cryonics advocacy organizations, and/or relevant research organizations.  However, these gifts can only help the individual patient if they are successfully cryopreserved in the first place, and a cryonicist can use their will to promote that crucial objective as well.  In her article, “How to Protect Your Cryonics Arrangements from Interference by Third Parties”, Rebecca Lively discusses the use of “no contest” clauses in wills as financial dis-incentives to interference by next-of-kin.

“No contest” clauses are also known as in terrorem[1] clauses, or forfeiture clauses – but in terms of will construction, these clauses are actually conditional gifts, that is to say, gifts that are conditional on certain behaviour.  In the usual scenario, the trigger is contesting the will in some way: for example, applying to a court for a declaration that the will is invalid because the will-maker didn’t observe the proper formalities, or wasn’t competent to make a will at the time of its execution, etc.  A very simple forfeiture clause might read as follows: “I leave $50,000 to Mary unless she contests the validity of this Will or any part of it, in which case said $50,000 shall instead go to the Society for the Prevention of Cruelty to Animals.”  If that clause was in a cryonicist’s will, which also contained his/her consent to body donation and/or instructions regarding disposition of human remains[2] (or incorporated those directions by reference to documents outside the will[3]), then contesting the will or the validity of the consent or instruction would trigger the condition and the gift to Mary would lapse and go to the SPCA instead.  However, there are plenty of ways that next-of-kin can interfere with prompt stabilization and cryopreservation without making legal contest so, as Lively suggests, it may be wise to draft the triggering condition to include other forms of interference.  Of course, the difficulty with going beyond the categories courts are familiar with is the risk that, if challenged, a creative condition might be deemed void for uncertainty.  For instance, what quantum of delay in contacting a patient’s cryonics organization constitutes “interference”?  The answer to this question will vary by circumstance.  No doubt for this very reason, Lively suggests drafting such a clause to provide for “inheritance on a sliding scale based on the amount of time which passes between your legal death and your cryopreservation”[4], where, presumably, the entire estate goes to charity/cryonics organizations if the will-maker is not cryopreserved at all.  However, given the many factors that can contribute to delay or non-preservation over which the beneficiaries have little to no control, that kind of inflexible forfeiture clause might come across as unfair and have the undesirable effect of promoting legal interference with the patient’s will in circumstances that are already sub-optimal for other reasons.  A better alternative might be to draft a forfeiture clause that is triggered by intentional interference, the presence of which (whether by act or omission/delay) is to be decided by an expert delegate with no direct interest in the matter, with at least partial reference to specific criteria described in the will.[5]

The degree and requirements of enforceability of forfeiture clauses vary considerably from place to place.  One jurisdiction might require a “gift over” to a specific beneficiary (like the example above)[6], while another might hold valid a forfeiture clause where the gift simply lapses into the residue of the estate.[7]  As Rebecca Lively points out, forfeiture clauses are not allowed at all in Florida and Indiana[8], and in many jurisdictions where they are permitted, they will nevertheless not be enforced against beneficiaries who contest the will with “probable cause” (though this should exclude contests founded solely on hostility towards a deceased’s cryonics arrangements). Furthermore, if the will is contested successfully, and declared invalid, then the forfeiture clause goes along with the rest of it, and the next-of-kin will collect as per the jurisdiction’s intestate succession regime.  Finally, forfeiture clauses will be held void or unenforceable to the extent that they offend public policy.  For instance, some jurisdictions permit applications by a surviving spouse and/or children to “vary” a will that does not make adequate provision for them in the circumstances.[9] Strictly speaking, these support applications are not “contesting” the will, but in any case, a forfeiture clause that was drafted with the intent of foreclosing such applications may be held to be against public policy, and thus void.[10]

Support applications are not the only means whereby next-of-kin can avoid, or partly avoid the sting of a forfeiture clause.  Oregon (and thirty-nine other US states) allows a surviving spouse to opt for an “elective share” in lieu of what the deceased’s will gives them (or, presumably, doesn’t give them).[11]  The right to make this election can be waived by written agreement[12], so it stands to reason that a forfeiture clause written to exclude from the estate any person who interfered with the will-maker’s cryonics arrangements, would be declared void to the extent that it attempts to cut off an interfering spouse’s statutory elective share.  Thus, even if a spouse’s actions trigger a forfeiture provision pertaining to a specific gift to them in the will, they will still be able to elect to receive this mandated share in the deceased’s estate.

Ten of the other states operate instead on a “community property” system[13] which, generally described, means that any earnings of either spouse or partner after marriage or registration of domestic partnership becomes “community property”, as does any property acquired with such earnings or with other money expressly or impliedly designated as “community funds”.[14] In Washington, a surviving spouse automatically gets half of all community property[15]. This cannot be avoided by will[16], nor does the statute provide for waiving this right.

So what’s the moral here?  Well, depending on where a cryonicist lives, and whether he/she is married or partnered and/or has children, the use of forfeiture clauses in a will to disincentivize interference with cryonics arrangements requires not just that those special next-of-kin are given “something substantial” to ensure their abidance (as Lively suggests), but that they are given something substantial above and beyond what they are entitled to under any statutory claims they can make which either (a) avoid the effects of the forfeiture clause, or (b) don’t trigger it in the first place.  A further difficulty, for those cryonicists living in jurisdictions with support order provisions, is that the size of such an order is based on consideration of the circumstances of the surviving spouse and/or children, the size of the estate, and non-specific statutory language like “necessary and reasonable”[17], or “adequate, just, and equitable”[18], so it is impossible to know on the face of the statute just how much is enough.  In many cases, the utility of forfeiture clauses as legal protection from interference will be greater for cryonicists who do not have living spouses or children, which is unfortunate given that those particular family members often pose the biggest threat.[19]

As a final note, wills may be used to transfer assets into a patient care trust or personal revival trust, which will be examined in the next section.  However, such funds would be better insulated from the estate if they were transferred during the cryonicist’s (first) lifetime.

Trusts

The basic premise of trusts is that legal ownership of property and the right to “enjoy” (i.e. benefit from) property can be separated, the former belonging to one person or group of persons (trustees), and the latter belonging to another person or group of persons (beneficiaries).  The duties of a trustee towards the beneficiary’s interests are more onerous than the duties of contracting parties, so trusts are often used to protect and provide for vulnerable persons, like minor children and spendthrift relatives.  For this reason, one would expect trusts to play a role in the legal protection of cryonicists, and indeed they do.  The two most prominent examples are patient care trusts and personal revival trusts.

(i) Patient Care Trusts

Patient care trusts promote the maintenance and revival of cryonics patients in two important ways.  First, transferring legal ownership of the assets provided to fund those objectives to trustees protects the assets from third-party litigants.  Second, patient care trusts protect those same funds from misuse by the cryonics organization itself and misappropriation by its directors or employees, and even the organization’s dissolution.

The most intuitive way of accomplishing these objectives would be to execute a trust under which present and future patients were beneficiaries.  However, because cryonics patients are dead, legally speaking, they have no legal personality and cannot be the beneficiaries of a trust.  Hence, while the terms of the Alcor Patient Care Trust (“APCT”) do state that Alcor is “acting on behalf of the Patients in biostasis”, Alcor is designated the sole legal beneficiary.[20]  Protection against third-party litigants is effected through the magic words, “[t]he interests of the beneficiary in principal or income shall not be subject to the claims of any creditor or to legal process, and may not be voluntarily or involuntarily alienated or encumbered”[21], together with the sections of the Arizona Trust Code upholding the validity of such provisions.[22]

The APCT’s ability to protect patient care funds from misuse, misappropriation, or potential dissolution of the organization ultimately boils down to whether (or how easily) Alcor, as the sole legal beneficiary, can simply terminate the trust and reclaim legal ownership of the funds.  The only termination scenario contemplated by the APCT (wherein Alcor still exists[23]), is if all the patients are revived and reintroduced to society.  All of the Arizona Trust Code provisions addressing modification or termination of charitable purpose trusts (like the APCT[24]) require that the court hearing the application consider whether modification or termination is consistent with the purposes of the trust and, if the trust is terminated, that the trust property be distributed by the trustees in a manner consistent with the purposes of the trust.[25] Practically speaking, it would be very difficult for Alcor to appropriate the patient care trust funds for any purpose other than patient care.

The APCT was established in 1997 and became irrevocable in 1999. The Cryonics Institute (“CI”) established an Endowment Care Trust Fund in 2004, as part of its agreement with Michigan’s Department of Energy, Labour, and Economic Growth to become licensed and regulated as a cemetery.  According to the conditions of licensure, “[t]hese funds will be set aside for maintenance, which shall include liquid nitrogen storage of existing CI patients.”[26]  Obviously the scope of this trust is not as ambitious as the APCT (nor was it intended to be), but it does protect at least some of the assets earmarked for patient care from misuse or misappropriation.[27]

(ii) Personal Revival Trusts

In his article, “Personal Revival Trusts: If You Can’t Take It with You, Can You Come Back To Get It?”, Igor Levenberg points out that for all the benefits of patient care trusts, “those who are revived will eventually have to provide for their own care.”[28]  Patient care trusts provide legal protection for cryonics patients’ interests at an organizational level, but those who are interested in additional protection – during their time as cryonics patients as well as post-revival – can establish personal revival trusts for this purpose.

To some extent, personal revival trusts (aka reanimation trusts) suffer from the same legal hindrance as general patient care trusts, namely that the individual cryonics patient cannot simply name themselves beneficiary of the trust because upon cryopreservation they will lose their legal personality, and the trust would revert back to their estate.  However, Levenberg describes two ways a cryonicist can draft themselves into a trust that don’t require proof at the outset that human cryopreservation is reversible.  One option is that the revived patient is a contingent beneficiary of the trust[29]; the other is that the patient’s revival is a condition subsequent which terminates the trust, with disbursement of the trust property to the revived patient[30].  The distinction is subtle, but bears important implications.  If the revived patient is named as the contingent beneficiary, the trust must have another beneficiary in the interim, who could potentially call for modification or termination of the trust.[31]  However, on such an application, the court will have to consider the patient’s contingent future interest, and may appoint a guardian to represent that interest.[32]  On the other hand, if the revival of the patient is a condition subsequent terminating the trust, the cryonicist could choose between a trust with an interim beneficiary, or a purpose trust with no interim beneficiary (like a charitable purpose trust, or a trust for the maintenance of one’s “grave”).[33] Purpose trusts have the additional advantage of being available for this use in jurisdictions which do not otherwise allow perpetual trusts.[34]

Levenberg suggests that any concern over the possibility of the interim beneficiary hijacking the personal trust for their own benefit can be cured by designating one’s cryonics organization in that role.[35]  With the right drafting, in a jurisdiction that places emphasis on the original terms and purpose of the trust, this may well work (as with the APCT, discussed above).  An added level of assurance can be effected through the use of trust protectors, relatively recently emerged characters in trust law who can be empowered by the trust to, among other things, grant beneficial interests to new individuals – like newly revived cryonics patients… or newly legally recognized cryonics patients.[36]  Trust protectors feature in many of the personal revival trusts under development, including the Alcor Model Trust.[37]

Trusts clearly play an important role in the legal protection of cryonics patients.  However, on a critical note, it must be remembered that not all problems have financial solutions.  Cryonics patients benefit greatly from secure financial vehicles to support their continued maintenance, fund resuscitation research, and even revert to them if and when they are reanimated, but if the care of a particular patient or group of patients falls below reasonable standards due to negligent mismanagement, or is being threatened by hostile governmental policy, what can trustees really do?  Neither patient care trusts nor personal revival trusts have any means of exerting direct control over the patients themselves, regardless of circumstance.


Endnotes:

[1] Latin: “in fear”.

[2] Remember that these are actually separate legal mechanisms for transfer of custody of human remains. See Keegan Macintosh, “Legal Protection of Cryonics Patients, Part 1” Depressed Metabolism (23 February 2012), online: Institute for Evidence Based Cryonics <http://www.evidencebasedcryonics.org>.

[3] See e.g. Last Will and Testament for Human Remains and Authorization of Anatomical Donation, online: Alcor Life Extension Foundation <http://www.alcor.org/Library>.

[4] Rebecca Lively, “How to Protect Your Cryonics Arrangements from Interference by Third Parties”, online: Alcor Life Extension Foundation <http://www.alcor.org/Library>.

[5] This should be available in at least some jurisdictions.  See Re Tuck’s Settlement Trusts, [1977] EWCA Civ 11.

[6] Bellinger v Nuytten Estate, 2003 BCSC 563 [Bellinger].

[7] Peter G Lawson, “The rule against in terrorem conditions: What is it – Where did it come from – Do we really need it?” (2005) 25 ETPJ 71 at 80-81.

[8] Supra note 4.

[9] See Wills Variation Act, RSBC 1996 c 490, s 2; see also ORS § 114.015.

[10] See Kent v Mackay, [1982] 139 DLR (3d) 318 at para 20 (BC SC) (available on WL Can): “It is a matter of public policy that support and maintenance be provided for those defined individuals and it would be contrary to such policy to allow a testator to circumvent the provisions of the Wills Variation Act by the creation of such as [the no contest clause here].  It is important to the public as a whole that widows, widowers and children be at liberty to apply for adequate maintenance and support in the event that sufficient provision for them is not made in the will of their spouse or parent.”  This decision was followed by the court in Bellinger, supra note 6.

[11] ORS § 114.600.

[12] ORS 114.620.

[13] Leaving Georgia, which only provides a surviving spouse (along with any minor children) one year’s allowance from the deceased’s estate: OCGA § 53-3-1.

[14] See, for example RCW § 26.16.030.

[15] RCW § 11.02.070.

[16] RCW § 26.16.030(1).

[17] ORS § 114.015.

[18] Wills Variation Act, supra note 9.

[19] Mike Darwin, “Marcelon Johnson dies and is not cryopreserved” Depressed Metabolism (24 January 2009), online: Institute for Evidence Based Cryonics <http://www.evidencebasedcryonics.org>. See also supra note 4.

[20] Alcor Patient Care Trust, online: Alcor Life Extension Foundation <http://www.alcor.org/Library>.

[21] Ibid, art 3.

[22] ARS § 14-10502. These clauses are called “spendthrift provisions” due to their use in trusts drafted to support persons with bad borrowing habits.

[23] If Alcor ceases to exist, and the APCT cannot be converted into an independent legal entity, then the funds will be disbursed to another organization, or by some other means further the purposes of the Trust to support the care, revival, and rehabilitation of Alcor patients. See supra note 20, art 17.

[24] While Alcor drafted the APCT to be consistent with its 501(c)(3) status, whether the APCT is in fact a charitable purpose trust concerns the application of ARS § 14-10405(A). Framing the purpose of the trust in terms of scientific research and education is not necessarily conclusive of the matter.

[25] ARS § 14-10410, 14-10411, 14-10413, and 14-10414.  Not all jurisdictions mandate as strong deference to the original terms of the trust; see, for example, Trust and Settlement Variation Act, RSBC 1996 c 463.

[26] Ben Best, “Conditions to Licensure as a Cemetery” The Immortalist (March 2004), online: Cryonics Institute <http://www.cryonics.org/immortalist>.

[27] The assets designated for patient care on CI’s 2011 year-end financial report amount to more than double the contents of the Endowment Fund: Statement of Assets, Liabilities, and Fund Balance, online: Cryonics Institute <link:http://cryonics.org/financials.html>.

[28] Igor Levenberg, “Personal Revival Trusts: If You Can’t Take It with You, Can You Come Back To Get It?” (2009) 83:4 St John’s Law Review 1469 at 1494, n 129.

[29] Ibid at 1489.

[30] Ibid at 1495.

[31] Ibid.

[32] Ibid at 1489-90.

[33] Ibid at 1498.

[34] Ibid.

[35] Ibid 1495-96.

[36] See e.g. ARS § 14-10818(C)(1).

[37] Ben Best, “Asset Preservation Group Meeting” Long Life (July 2011) 23 at 24, online: Cryonics Institute <http://www.cryonics.org/immortalist>; see also Ben Best, “Fourth Asset Preservation Group Meeting” Depressed Metabolism (2 June 2010), online: Institute for Evidence Based Cryonics <http://www.evidencebasedcryonics.org>.

22. March 2012 · Comments Off · Categories: Cryonics

One of Alcor’s founders, Fred Chamberlain III, has been cryopreserved at Alcor. His wife, and co-founder of Alcor, Linda Chamberlain, has released a document to announce his cryopreservation and honor him:

“One of our great intellectual and emotional bonds was our interest in technological means of extending life. Fred and I incorporated the Alcor Life Extension Foundation in 1972; the minutes of those early Alcor meetings can be viewed by those who might be interested. Many details from those early years are available on Wikipedia.”

Fred and Linda were also supporters and occasional contributors to the Depressed Metabolism blog, and contributed one of the first articles about how modern cell phones can be used to communicate your cryonics arrangements in case of an emergency.

More accounts of Fred’s contributions to cryonics and Alcor should be forthcoming soon.

06. March 2012 · Comments Off · Categories: Cryonics

On Saturday July 7, 2012, the Institute for Evidence Based Cryonics and Cryonics Northwest will organize a symposium on cryonics and brain-threatening disorders in Portland, Oregon. The symposium will start at 09:00 am at the offices of Kaos Softwear. Entrance to the event is free.

This symposium is the first event of its kind in the history of cryonics and concerns one of the most important challenges facing aging cryonicists. Please register for the event on our Facebook page so we know how many attendees to expect.

The following speakers and presentations are confirmed and more speakers / activities may be added in the future:

Chana de WolfNeurogenesis in the Adult Brain and Alzheimer’s Disease

Early neuroanatomists considered the adult brain fixed and incapable of neurogenesis. Chana de Wolf will review the emerging evidence for adult neurogenesis and its implications for the treatment of Alzheimer’s disease and other identity-destroying disorders.

Chana de Wolf has a master’s degree in Neuroscience and is the President of Advanced Neural Biosciences, Inc.

Aubrey de Grey, Ph.D. – Repairing the Aging Brain: The SENS Approach

Like all other organs, the brain accumulates molecular and cellular alterations throughout life that are eventually deleterious to its function. Unlike all other organs, it cannot be replaced wholesale by a new one created in the lab; the damage must be repaired piecemeal. In this talk I will survey the current status of repairing the three major forms of damage seen in the brain of elderly people: the amyloid plaques that accumulate in the extracellular space in Alzheimer’s disease, the various intracellular proteinaceous aggregates seen in all the major forms of neurodegeneration, and the loss of neurons of various types seen in the advanced stages of Alzheimer’s, Parkinson’s and in aging in general. Relevance to revival of cryonics patiends and to certain schemes for uploading will also be discussed.

Dr. Aubrey de Grey is a biomedical gerontologist based in Cambridge, UK, and is the Chief Science Officer of SENS Foundation, a California-based 501(c)(3) charity dedicated to combating the aging process. He is also Editor-in-Chief of Rejuvenation Research, the world’s highest-impact peer-reviewed journal focused on intervention in aging. He received his BA and Ph.D. from the University of Cambridge in 1985 and 2000 respectively. Dr. de Grey is a Fellow of both the Gerontological Society of America and the American Aging Association, and sits on the editorial and scientific advisory boards of numerous journals and organisations.

Ben Best – Drugs, Supplements, and other Treatments to Mitigate and Prevent Alzheimer’s Disease

In the United State over 40% of people over age 84 develop Alzheimer’s Disease. Death by Alzheimer’s Disease for a cryonicist could mean death in the absolute sense, even if cryopreserved under the best of circumstances. Ben Best will discuss drugs, supplements, and other treatments to mitigate and prevent Alzheimer’s Disease, discussing the relevance of these preventative/mitigating agents to probable causes of Alzheimer’s Disease.

Ben Best has bachelor’s degrees in Pharmacy, Physics, Computing Science and Business (Accounting and Finance). He is President of the Cryonics Institute and has done extensive self-study of mechanisms of aging in general and Alzheimer’s Disease in particular.

Mike Perry, Ph.D. – Early Detection of Alzheimer’s Disease: Some Recent Progress

A new study has doubled the time interval for the first detectable changes in the brain of a person with Alzheimer’s disease (AD): from five years to ten years before dementia occurs.  Mike Perry will report on this advance and other progress that offers the possibility of both earlier detection and more effective treatments for AD.

Mike Perry has a Ph.D. in computer science and is the Care Services Manager at Alcor Life Extension Foundation. His book, Forever for All, offers a moral argument for the pursuit of life extension through cryonics, with an optimistic conclusion about the scientific prospects for immortality.

Max More, Ph.D. – Survival, Identity, and the Extended Mind

Can personal identity be reduced to the brain? If it cannot, does this offer challenges or advantages for cryonics? And what is the relevance of the concept of the extended mind for brain-threatening disorders such as Alzheimer’s disease? Alcor President Max More reviews recent theories about the mind and identity and their implications for personal survival.

Max More is the President & Chief Executive Officer of the Alcor Life Extension Foundation. More has a degree in Philosophy, Politics, and Economics from St. Anne’s College, Oxford University (1984-87). He was awarded a Dean’s Fellowship in Philosophy in 1987 by the University of Southern California. He studied and taught philosophy at USC with an emphasis on philosophy of mind, ethics, and personal identity, completing his Ph.D. in 1995, with a dissertation that examined issues including the nature of death, and what it is about each individual that continues despite great change over time.

01. March 2012 · Comments Off · Categories: Cryonics, Neuroscience

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

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

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

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

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

In a previous article, Aschwin de Wolf argues that it might be easier to persuade others that cryonics patients are still alive according to existing criteria of death, than to argue for the adoption of a more progressive definition, such as information-theoretic death.  Presumably though, if we are to go to the trouble at all, it will not be solely to alleviate our subjective discomfort with the idea of being labelled dead, but rather because achieving such recognition would accrue practical benefits to present and future cryonics patients.  While it may seem obvious to state that living persons enjoy greater legal protection than dead ones, it would be inaccurate to base a comparison of the two on the assumption that, for cryonics purposes, the dead are not protected by the law whatsoever.  The question, then, is what legal protections do cryonics patients currently have, and are they enough?

First of all, what exactly does “legal protection” mean in this context? As a working definition, let’s say for the moment that we are looking for:
(a) social coercion mechanisms that promote the success and timeliness of a person’s cryopreservation, maintenance, and resuscitation, that
(b) persist after he/she has been declared dead,
(c) the ultimate authority of which flow from a jurisdiction’s laws through its courts, police, and other state agents.

(At this point, it should be pointed out that this article is not meant to be an exhaustive review, and is certainly not intended as legal advice, and so should not be relied on as such. It is solely intended as food for thought and further discussion.  The reader will also notice a distinctly Canadian perspective, and it will become apparent that generalization to other jurisdictions is not always possible. The author apologizes; it is simply the system with which he is most familiar.)

The right to a decent burial…

A corpse is not a person anymore, legally speaking, and does not have rights as such, but nonetheless there are legal obligations regarding the corpse which are imposed on still-living persons that derive from its former humanity and personhood.  Recognition of and support for prospective autonomy exist in tension with providing for the material and emotional needs of the living, as well as general social discomfort with the idea of reducing the physical remains of a former person to simple property that is owned by another.  Thus, very different kinds of rules apply to physically dealing with the corpse than apply to property owned by the person the corpse once was (property here encompassing both tangible property, and intangible “property”, like rights to another party’s performance of their obligations under a contract, etc).

The process of getting the deceased’s remains to an appropriate resting place (i.e. somewhere out of view and where it will not endanger the health of others) is partly addressed by criminal law.  Section 182(a) of Canada’s Criminal Code makes it an offence to neglect, without lawful excuse, to perform any duty imposed by law or undertaken with reference to the burial of a dead body or human remains.[1]  This is an indictable offence (roughly equivalent to a felony in the US) carrying a maximum penalty of five years imprisonment, but while prescribing this penalty for neglect of duty to bury, the Criminal Code does not itself create any such duty.  The source of the duty to bury is the common law, which calls for the executor or appointed administrator to ensure a dignified burial, or more specifically, a burial “befitting the deceased’s station in life”[2], and the term “burial” in this context has been broadly interpreted to include other forms of interment, as well as cremation.

Other aspects of the common law duty have been codified in and altered by provincial statutes.  In British Columbia, some important details can be found in the Cremation, Interment and Funeral Services Act.[3] Section 5 of the Act vests the right to control the disposition of human remains in the personal representative (read: executor) named in the deceased’s will, if any, and otherwise in the deceased’s spouse or next-of-kin.    Failing that, a government ministry may take charge, or else an unrelated person who was close to the deceased.  The person at the top of the list is not compelled to give instructions, however; if he/she is unavailable or unwilling, the right to control disposition passes to the next person in the list until someone agrees to take on the responsibility.  If multiple persons of the same degree of consanguinity cannot agree as to who among them has priority, the eldest of them takes it.[4]  A person may also apply to a court for priority irrespective of their relationship to the deceased, and on such an application the court must consider the feelings of the deceased’s relatives and associates, the beliefs and practices of others of their religion (if any), any relevant directions by the deceased, and whether the application concerns family hostility or a “capricious change of mind” regarding disposition of human remains.  The moral for cryonicists: make your intentions known early, widely, and often.

Once the person with the right to control disposition has been identified by section 5, section 6 of the CIFSA obliges him/her to exercise that right in accordance with any preference of the deceased written in their will or pre-need funeral services contract.  This is subject to a couple of important provisos, however.  First, a written preference of the deceased is not binding if compliance with the preference would be unreasonable, impracticable or cause hardship.[5]  Arizona’s analogous provision omits “impracticable”, and specifies hardship as economic or emotional.[6]  In either case, it is also probably inferable that the deceased’s instructions are only binding if they are otherwise lawful.  In Michigan, on the other hand, the deceased’s preferences are not binding on the person(s) with the right to control disposition, and neither Arizona nor Michigan gives the personal representative named in the will priority over next-of-kin in these matters, though Arizona does give priority over next-of-kin (but not over any spouse) to a person designated under a durable power of attorney.[7]  In light of this, it is rather fortunate that Robert Ettinger’s children supported his wish to be cryopreserved.[8]

Looking again at the BC law, the second exception to the duty to comply with a written preference of the deceased, is that compliance with the preference must be consistent with the Human Tissue Gift Act.[9]  Thus, a statutorily valid consent to donate one’s body or part thereof for therapeutic purposes, medical education, or scientific research will prevail over a contrary intention stated in the will or contract.[10]  The HTGA also states that upon death, such consent is “binding and full authority for the use of the body or the removal and use of the specified parts for the purpose specified”.[11]  This is a very broad authority compared to s.6 of the CIFSA, above, which only binds the person with the right to control disposition.  While the true legislative object here is almost certainly to hasten the organ transplant process by eliminating all possible sources of interference, this human remains transfer mechanism could be utilized by cryonicists in British Columbia analogously to the various state enactments of the Uniform Anatomical Gift Act in the US.  However, this does not mean that cryonicists would be advised to rely entirely on a signed body donation consent form, and not speak to the issue in their will, because if, for some reason, the donation mechanism fails (perhaps because the patient’s home jurisdiction refuses to recognize the cryonics service provider’s activities as scientific research), the disposition mechanism will operate in default to the same end.[12]  This is not a purely hypothetical concern: section 3(4) of Alberta’s equivalent to the HTGA states that only a university with a medical, dental or related health program may use a body donated under that Act for medical education or scientific research.[13]  Read in harmony with the rest of the Act, this rules out at minimum full-body donations to Cryonics Institute or Alcor.[14]  Whether the use of “body” in that section includes organs/parts, thus preventing head-only donations to Alcor as well is less clear.  Other sections of the Act refer to “any tissue, organs, or body”, so it could be argued that by negative implication the use of “body” on its own in s.3(4) refers only to donations of entire human bodies, permitting a workaround for members of Alcor who opt for neuropreservation. On the other hand, a court could decide the omission was a mere drafting error, and/or interpret the section ‘purposively’, if persuaded that the legislative intent was to restrict donation of tissues and organs in the same way as whole bodies.  If that were to be the case, Albertan cryonicists’ would be entirely restricted to the disposition mechanism for transfer of human remains.  Even more unfortunately, the preferences of the deceased with respect to disposition of their human remains are not binding on their personal representative or next-of-kin[15], so newly deanimated cryonics patients in Alberta are not at all protected in this regard.

At English-Canadian common law, historically speaking, the preferences of the deceased were not binding on executors because of a then well-accepted legal principle that there is no property in a corpse.[16] That is to say, because a person’s body was not owned by them in the legal sense, it wasn’t something that could be disposed of by a deceased in their will.  Written preferences of this kind being legally binding is something of an innovation in Canadian law[17], and might provide unexpected legal protection for cryonics patients, namely that if a deceased’s written instructions regarding disposition are binding on the person with the right to control disposition, then acting contrary to those instructions (without a lawful excuse like unreasonableness or hardship) is criminal neglect of duty per s.182(a) of the Criminal Code, as discussed above.  Thus, in of all places, British Columbia, hostile spouses, next-of-kin or poorly chosen executors could actually be criminally liable if they impede or neglect to facilitate their dearly-departed’s cryonics arrangements, although whether the police and prosecutors would decide there was a public interest in pursuing the matter is a different question entirely.  Furthermore, it doesn’t stretch the imagination to envision arguments that cryopreservation is unreasonable, or imposes some kind of hardship, and whether or not such excuses ultimately fail cannot repair the damage caused by the delay.  Nevertheless, it is clear that, with regards to the initial transfer of remains for cryopreservation, different jurisdictions offer varying types and levels of legal protections for cryonics patients.

The right to quiet repose…

Coincident to the executor’s (or other’s) duty to bury is a right of possession in the human remains, and this persists even after burial for the very practical reason that, otherwise, “those who oppose the executor would disinter the body as soon as it was buried.”[18]  That said, there are other, broader sanctions against disturbing human remains, both before and after burial.  Section 182(b) of the Criminal Code prohibits improper or indecent interference with, or offerings of indignities to a dead human body or human remains, punishable by up to five years imprisonment (like s.182(a), above).[19]  In Arizona, unauthorized disinterment or “mutilation” of human remains is a felony punishable up to 3.75 years for a first offence[20]; in Michigan, meanwhile, the maximum punishment for same is 10 years or $5000, and includes “defacing” of human remains as well.[21]  At first glance it seems strange that the Canadian provision doesn’t simply proscribe unauthorized or unlawful interferences with human remains.  Does this not imply that there are ways a person could intentionally interfere with human remains that, while not legally authorized, are nevertheless not improper or indecent?  The Criminal Code is not the whole picture, however; provincial legislation picks up where it leaves off.  The CIFSA prohibits unauthorized disinterment of human remains, with a maximum penalty of 12 months or $10,000.[22]

Though crafted to protect the corpse’s ‘right’ to non-interference (or perhaps the still-livings’ desire not to be confronted with evidence of the helplessness of mortality), section 182(b) could conceivably work contrary to cryonics patients’ interests as well, depending as it does on prevailing notions of decency, propriety, and human dignity.  The wishes of the deceased are only one part of the matrix of circumstances which will be considered in determining whether a particular interference was improper, etc.  By analogy, consent is not available as a defence to all criminal charges.  Nevertheless, the chances of a perfect storm arising of anti-cryonics police, prosecutors, judge and jury, resulting in a finding that cryopreservation is an affront to human dignity, seem remote.  The terms “mutilate” and “deface” are not themselves entirely value-mute, but the Arizona and Michigan provisions are more specifically circumscribed to leave standards of propriety in this area to the funeral industry[23]; and as before, body donations to research probably avoid these provisions entirely, though there is potential for complication when the cryonics service provider is regulated as a cemetery.

Whether the penalty at the other end of the law is a deprivation of liberty, property, or both, the best outcome from the perspective of the cryonics patient is no interference in the first place, so the best legal protection in that sense is the threat of such deprivations.  Unfortunately, all the rules discussed so far that may promote an individual’s cryopreservation and maintenance are limited by ‘lawful authorization’ exceptions, and thus whatever ‘rights’ a cryonics patient may be said to have against interference with their care are only public relations/political considerations if there is another pressing public need to be addressed.  Ascertaining a person’s cause of death when such is unclear tends to trump all else; in BC, even the Human Tissue Gift Act is expressly subject to the Coroner’s Act.[24]  The historical mandate of the coroner was to “speak for the dead”, and one must wonder if such a function is truly necessary when the “dead” has done a reasonably good job speaking for him/herself by making cryonics arrangements, the objective of which is clearly endangered by autopsy.  Cryonicists in the five US states which have enacted religious objection to autopsy legislation (California, New Jersey, New York, Ohio and Rhode Island) may find some relief by that route, but common to these is the ability for the coroner/medical examiner to override the objection where an autopsy is deemed necessary as part of a criminal investigation, or to meet an “immediate and substantial threat to the public health”.[25]  Those laudable public interests seem less compelling if there is a chance that the objector’s death is only a serious, but ultimately curable trauma (if stabilization procedures are allowed to begin right away, that is) but as discussed at the outset, that kind of argument relies on the adoption of a new definition of death, or the recognition of cryonics patients as alive according to the current one, which would result in cryonics patients having a substantially different set of legal protections than presently under examination…

Still to come: wills and trusts.

Endnotes (hyperlinked where possible):

[1] Criminal Code, RSC 1985, c C-46 s 182(a).

[2] Tzedeck v Royal Trust Co, [1953] 1 SCR 31 at 37.

[3] Cremation, Interment and Funeral Services Act, SBC 2004, c 35 (“CIFSA”).  Section 14 of the CIFSA prohibits the sale and marketing of cryonics arrangements in the province, but readers should note that Consumer Protection BC has issued an interpretation guideline stating that section 14 does not prohibit cryonics arrangements with service providers outside the province, nor does it prohibit local funeral directors from providing preparation and transport services related to such arrangements.

[4] Michigan and Arizona take a majority-rules approach: MCL § 700.3206(4) and ARS § 36-831(D).

[5] CIFSA, s 6(c).

[6] ARS § 36-831.01(A).

[7] MCL § 700.3206, ARS § 36-831(A).

[8] There is no evidence from CI’s report of Ettinger’s cryopreservation that his son, David needed to commence legal action in lieu of majority agreement between siblings.

[9] CIFSA, s 6(b), referring to Human Tissue Gift Act, RSBC 1996, c 211 (“HTGA”).

[10] HTGA, ss 4(1), 5(1).

[11] HTGA, s 4(3).

[12] HTGA, s 8.

[13] Human Tissue and Organ Donation Act, SA 2006, c H-14.5.

[14] Ibid, s 3(1).

[15] General Regulation (Cemeteries Act), Alta Reg 249/1998.

[16] Williams v Williams (1882), 20 Ch D 659.

[17] Quebec is the only other province to grant such a right: art 42 CCQ.

[18] Waldman v Melville (City of) (1990), 65 DLR (4th) 54.

[19] Criminal Code, s 182(b).

[20] ARS § 32-1364.

[21] MCL § 750.160.

[22] CIFSA, s 19.

[23] Supra notes 20 and 21.

[24] HTGA, s 13(1), referring to Coroners Act, SBC 2007, c 15.

[25] Stephen Bridge, “The Legal Status of Cryonics Patients: An Introduction”.  Washington’s state Senate recently passed a similar bill as well.

22. February 2012 · Comments Off · Categories: News

The Institute for Evidence Based Cryonics website and the Depressed Metabolism blog have now been completely integrated.

In 2007 the Institute for Evidence Based Cryonics was established as a 501(c)(3) tax exempt non-profit organization to educate the general public about cryonics and launch projects to improve the science and practice of cryonics. The Institute publishes the Depressed Metabolism blog about cryonics and life extension, hosts the Scientists’ Open Letter on Cryonics, and runs two mailing lists about personalized cryonics and low cost personal survival technologies. In the near future we aim to launch a public wiki project to generate a knowledge database to assist in the resuscitation of existing cryonics patients.

The weekend of July 7 and July 8 the Institute for Evidence Based Cryonics and Cryonics Northwest will host a symposium on cryonics and brain-threatening disorders in Portland, Oregon. Confirmed speakers include Aubrey de Grey, Ben Best, Max More, Michael Perry, and Chana de Wolf. Please save the date. More details will be provided soon.

Regular posting on the Depressed Metabolism blog will resume tomorrow.

Introduction

Cryoprotectant toxicity should be distinguished from other mechanisms of cryopreservation injury such as chilling injury (injury produced by too low temperatures as such) and cold shock  (injury produced by rapid cooling). Cryoprotectant toxicity itself can again be divided into general cryoprotectant toxicity and specific cryoprotectant toxicity. General cryoprotectant toxicity involves concentration (water substitution) effects of cryoprotectants and specific cryoprotectant toxicity involves the effects of individual compounds on cellular viability. General cryoprotectant toxicity presents a formidable obstacle for cryopreservation methods that require very high concentrations of cryoprotectant agents (such as vitrification).

Another mechanism of injury that is rarely discussed in the cryobiology literature but that can complicate cryopreservation of complex organs is “non-specific” dehydration injury. In light of the fact that the current generation of vitrification agents are delivered in hypertonic carrier solutions and contain non-penatrating cryoprotective agents which do not cross the blood brain barrier, this form of damage may be especially important in cryopreservation of the brain.

Systemic reviews of cryoprotectant toxicity are rare but some mechanisms for (specific) cryoprotectant toxicity have been proposed including, but not limited to, protein denaturation, modification of biomolecules, membrane injury, destabilization of the cytoskeleton, oxidative damage, and ATP depletion. It is important to stress that some of the mechanisms may be downstream effects of other mechanisms. For example, ATP depletion can cause oxidative damage. And as Gregory Fahy has pointed out, cryoprotectant toxicity should be distinguished from injury associated with the method of introduction and washout of the cryoprotectant. In 2004, Fahy, Wowk et al., proposed a compositional variable to predict general cryoprotectant toxicity.

Cryoprotectant toxicity can also vary by species and organ type. Cryoprotectants that are moderately toxic in one species can be highly toxic in others. Similarly, cryoprotectants that are moderately toxic in one organ can be highly toxic in others (or even between different types of cells within organs). This raises the question of whether universal non-toxic cryoprotective agents are attainable (a requirement for reversible vitrification in complex organisms).

Cryoprotectant toxicty can be investigated by cryopreserving an organ (or cell) and measuring its viability after rewarming and washout of the cryoprotective agent. To eliminate the influence of other mechanisms of injury associated with cryopreservation (such as ice formation), a cell can just be loaded and unloaded with the cryoprotectant without cryopreservation. The effects of hypothermia on viability can be eliminated altogether by normothermic perfusion of the organ. This, of course,  introduces a challenge for hypoxia sensitive organs such as the heart and the brain because cryoprotective agents may not be good oxygen carriers.

Papers

Baxter SJ, Lathe GH (1971). Biochemical effects of kidney of exposure to high concentrations of dimethyl sulphoxide.
Biochemical Pharmacology. Jun; 20(6): 1079-91.

Baxter and Lathe investigated the effect of high concentrations of DMSO on kidney preparations. In a series of illuminating experiments, the investigators established that anaerobic glycolysis was reduced in slices and homogenates as a result of increased activation of the gluconeogenesis enzyme Fructose 1,6-diphosphatase (FDPase). DMSO-induced activation of FDPase can be inhibited by adding an amide or lysine to DMSO. The finding that a combination of DMSO and an amide allows for less toxic cryoprotectants formed the basis of subsequent investigations of GM Fahy for potent vitrification solutions.

Fahy GM (1983). Cryoprotectant Toxicity Neutralizers Reduce Freezing Damage.
Cryo-Letters 4: 309-314.

In this paper GM Fahy reports the ability of toxicity neutralizers urea, formamide, and acetamide (all amides) to reduce injury of cryopreserved renal cortical slices with DMSO. In later research papers Fahy will establish that DMSO neutralizes the toxicity of formamide, and not the other way around.

Fahy GM (1984). Cryoprotectant toxicity: biochemical or osmotic?
Cryo-Letters 5: 79-90.

If osmotic stress is an important cause of injury during introduction and removal of cryoprotectant agents, improved viability can be obtained by reducing the rate of cryoprotective agent introduction and removal. Fahy reviews the literature and presents data obtained in renal cortical slices that indicate that substantial hypertonic osmotic stress does not produce major changes in viability. Conversely, reducing exposure time to higher concentrations of the cryoprotectant can contribute to improved viability. These results suggest that biochemical toxicity, not osmotic stress, is the major factor in cryoprotectant-induced injury.

Fahy GM (1984). Cryoprotectant toxicity: specific or non-specific?
Cryo-Letters 5: 287-294

Fahy reviews the argument (Morris, Cryoletters 4, 339-340, 1983) that the lower toxity of cryoprotectant solutions that contain DMSO and amides can be entirely explained by the lower absolute concentration of DMSO. Fahy points out that the original Bexter and Lathe experiments demonstrated that solutions with the same absolute amount of DMSO (4.6 M) but with or without amides had different effects on glucose utilization. The author also presents data showing that “simple substitution (“dilution”) of one agent for another strikingly fails to reduce overall toxicity over a very critical range of DMSO concentration.” Also briefly discussed is the possibility of mutual toxicity neutralization between DMSO and amides, a topic that would be further explored by Fahy in future research.

Fahy GM, MacFarlane DR, Angell CA, Meryman HT (1984). Vitrification as an approach to cryopreservation.
Cryobiology.  Aug ; 21(4): 407-26.

In this paper on vitrification as an alternative to conventional cryoprotection, Fahy et al., list a number of methods for reducing cryoprotectant toxicity:

Primary (direct) methods:

  1. Maintain temperature as low as possible;
  2. Select an appropriate carrier solution;
  3. Keep exposure time at higher concentrations to a minimum;
  4. When possible, employ specific cryoprotectant toxicity neutralizers.

Secondary (indirect) methods:

  1. Avoid osmotic injury;
  2. Mutual dilution of cryoprotectants may be helpful in some instances;
  3. Use extracellular cryoprotectant to reduce exposure to intracellular cryoprotectant when possible.

The most important insights, some of which are still maintained in the current generation of vitrification solutions, concern toxicity neutralization, the choice of an appropriate carrier solution, and the use of extracellular cryoprotectants.

Fahy GM (1986). The relevance of cryoprotectant “toxicity” to cryobiology.
Cryobiology. Feb; 23(1) :1-13.

Fahy presents evidence that cryoprotectants themselves can present a source of injury. As a consequence, the advantages of higher concentrations of the cryoprotective agents does not necessarily produce higher viability after freezing, even when this allows for greater ice inhibition. He reviews data on “cryoprotectant-associated freezing injury” for DMSO, ethylene glycol, methanol, ethanol, and glycerol.  Because vitrification requires very high concentrations of cryoprotective agents, toxicity is the key limiting factor in reversible vitrification of organs.

Fahy GM, Lilley TH, Linsdell H, Douglas MS, Meryman HT (1990). Cryoprotectant toxicity and cryoprotectant toxicity reduction: in search of molecular mechanisms.
Cryobiology. Jun; 27(3): 247-68.

Fah,y et al., delineate 6 criteria that must all be met simultaneously in order for a putative mechanism of cryoprotectant toxicity to be implicated:

  1. The relationship between observed biochemical alteration and cellular viability must be clear or easily plausible;
  2. The maginitude of the cryoprotectant effect must be large enough to be significant;
  3. The effect must be irreversible over a reasonable time span after removal of the cryoprotectant;
  4. The time course of the observed effect must be consistent with the time course of observed injury;
  5. The cryoprotectant effect must be possible under conditions that could reasonably be encountered inside a living cell being prepared for freezing or being subjected to freezing and thawing itself;
  6. The cryoprotectant effect must be due to the cryoprotectant itself and not due to the technique of introduction and washout.

The authors investigate the proposed mechanisms for the biochemical effects of DMSO toxicity in the 1971 Baxter study and find that a) the effect of DMSO on FDPase activation is too small to affect the normal respiration of the cell and therefore fails to meet criterion 2 to be a significant mechanism of cryoprotectant toxicity; b) the presence of formamide does not affect the interaction between DMSO and lysine; and c) toxicity is not consistently reduced by blocking alteration of FDPase rather than substituting those compounds for DMSO.

The authors further present results that do not support the theory that generalized  protein denaturation is related to cryoprotectant toxicity.  The article ends with a referenced list of phenomena possibly related to mechanisms of cryoprotectant toxicity.

Fahy GM, da Mouta C, Tsonev L, Khirabadi BS, Mehl P,  Meryman HT (1995). Cellular injury associated with organ cryopreservation: Chemical toxicity and cooling injury.
Editors: John J. Lemasters, Constance Oliver. Cell Biology of Trauma, CRC Press

Fahy, et al., review different mechanisms of cryoprotectant toxicity with a particular focus on DMSO-medicated chemical injury. Mechanisms discussed include fructose-1,6-bisphosphatase activation, sulfhydryl oxidation, activation of extracellular proteinases and endothelial cell detachment and death. The article lists a number of interventions that do not change CPA-medicated injury such as inhibition calcium mediated injury or protein denaturation. The authors also report how the toxicity of formamide can be completely reversed by addition of DMSO.

Bakaltcheva IB,  Odeyale CO, Spargo BJ (1996). Effects of alkanols, alkanediols and glycerol on red blood cell shape and hemolysis.
Biochimica et Biophysica Acta. 1280: 73-80

In this elegant and thoughtful paper, the authors use the human red blood cell to study cryoprotectant toxicity. Morphological observations, quantification of hemolysis, measurements of the dielectric constant of the incubation medium (Ds) and the dielectric constant of the erythrocyte membrane in the presence of organic solutes (Dm), are used to investigate cryoprotectant toxicity in a series of alkanols, alkanediols, and glycerol. The authors propose that toxicity of a cryoprotectant is related to its ability to change the ratio of Ds/Dm. Changes in this ratio reflect changes in the difference between hydrophobicity of the solution and the membrane, with decreases in this ratio leading to increased exposure of membrane surface area and vesiculation, and increases in this ratio leading to decreased exposure of membrane surface area and cell fusion. The authors suggest that the design of less toxic cryoprotective agents should involve the maintenance of dielectric homeostasis of the medium and the membrane. Their findings also throw light on the observation that combinations of various cryoprotectant agents (such as DMSO and formamide) can reduce the overall toxicity of a solution.

Fahy GM, Wowk B, Wu J, Paynter S (2004). Improved vitrification solutions based on the predictability of vitrification solution toxicity.
Cryobiology. Feb; 48(1): 22-35.

This seminal paper on non-specific cryoprotectant toxicity represents a major contribution to the cryobiology literature in general, and enabled the authors to formulate less toxic vitrification solutions for the cryopreservation of whole organs. In the paper the authors propose a new compositional variable that reflects the strength of water-cryoprotectant hydrogen bonding called qv*. Contrary to the cryobiology wisdom to date, the authors found that weaker glass formers favor higher viability. As a consequence, vitrification agents with higher concentrations of cryoprotective agents are not necessarily more toxic. Although qv* is not helpful in predicting specific cryoprotectant toxicity, this paper, and the research that is reflected in it, suggests that non-specific cryoprotectant toxicity is mediated through the effects of penetrating cryoprotectant agents on the hydration of biomolecules.