Response to Aschwin de Wolf's 'Evidence Based Cryonics'

In his article entitled ‘Evidence Based Cryonics’ Aschwin de Wolf unassailably argues that: “There is an urgent need to move from extrapolation based cryonics to evidence based cryonics. This will require a comprehensive research program aimed at creating realistic cryonics research models. It will also require vast improvements in the monitoring and evaluation of cryonics cases. The current debate should no longer be between advocates and opponents of standby and stabilization but about what stabilization procedures should be used by cryonics organizations given our current knowledge”.

Unfortunately, much of the rest of what he has to say is incomplete or lacks the necessary context required to allow for a fair and technically sound evaluation. Perhaps the brevity of the blog format was the reason for these shortcomings? In any event, I would like to comment on these remarks and provide a somewhat different perspective on the complex and important issues discussed in ‘Evidence Based Cryonics.’

The best place to start is to define what evidence based medicine is, and then proceed to attempt to describe what might constitute ‘evidenced based cryonics.’ Webster’s New World Medical Dictionary, 3rd Edition (2008) defines evidence-based medicine as, “the judicious use of the best current evidence in making decisions about the care of the individual patient. Evidence-based medicine (EBM) is mean to integrate clinical expertise with the best available research evidence and patient values. EBM was initially proposed by Dr. David Sackett and colleagues at McMasters University in Ontario, Canada.” Having defined what EBM is, the next question is, what constitutes “the best current evidence?”

The United States uses the U.S. Preventive Services Task Force (USPSTF) system for evaluating evidence about the effectiveness of medical interventions. The USPSTF classifies evidence in terms of reliability for use in decision making as follows:

* Level I: Evidence obtained from at least one properly designed randomized controlled trial.

* Level II-1: Evidence obtained from well-designed controlled trials without randomization.

* Level II-2: Evidence obtained from well-designed cohort or case-control analytic studies, preferably from more than one center or research group.

* Level II-3: Evidence obtained from multiple time series with or without the intervention. Dramatic results in uncontrolled trials might also be regarded as this type of evidence.

* Level III: Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees.

* While beyond the scope of discussion here, it is worth noting (and referencing) the work of Guyatt, et al., and the GRADE Working Group in further defining what constitutes the quality and strength of scientific evidence; a formidable and controversial task (1- 6).

* To anyone knowledgeable in the areas of medicine applicable to human cryopatient stabilization and transport procedures (i.e., resuscitation/reanimatology, ischemia-reperfusion injury, solid organ preservation, deep hypothermic cardiopulmonary bypass and whole animal asanguineous perfusion) it will immediately be apparent that none of the 5 classes of evidence presented above can be directly applied to cryonics cases. Arguably, Level III evidence, the “opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees” might apply were there any acknowledged ‘respected authorities’ in the sphere of cryonics standby, stabilization or transport patient care. Alas, no such authorities, respected or otherwise, are currently ‘acknowledged’ to exist.

Thus, the first statement Aschwin makes in opening his article, “Cryonics patients can greatly benefit from rapid stabilization after pronouncement of legal death,” which he defines as “procedures that aim to rapidly restore blood circulation and drop the patient’s temperature” is itself unsupported by either conventional medical research or by cryonics research or case reporting using EBM criteria. If the information-theorertic criteria, as validated by ultrastructural preservation of the brain (7), or the demonstrated recovery of function of the brain are to be used as the gold standards for determining the efficacy of cryonics stabilization and transport procedures, then there currently exists no EBM quality (scientifically robust) data to support “restoration of blood circulation” following pronouncement of medico-legal death in cryopatients.

More specifically, assuming such an intervention is warranted, the question then becomes,’ under what circumstances and in which patients should it be applied?’ Is the patient with 30 minutes of post-arrest warm ischemia better off with simple external cooling followed by cryoprotective perfusion, as opposed to undergoing in-the-field reperfusion using closed chest cardiopulmonary support? What about the patient with profound peri-arrest hypoperfusion with evidence of failed or inadequate brain perfusion, such as the presence of fixed and unresponsive pupils for many minutes, or even for an hour or more, before cardiac arrest occurs and medico-legal death can be pronounced? At what point in the complex and difficult to quantify spectrum of warm ischemic injury should cardiopulmonary support be withheld? Or, given that the benefits of rapid post arrest cooling are unequivocally supported by Level II-2 and Level II-3 evidence from conventional medicine, should such support be modified to mitigate or prevent oxygen-driven reperfusion injury by carrying out CPS under anoxic conditions, and if so, under what circumstances and by what procedures? We have no rigorous answers to these questions and Aschwin is certainly on-point in calling for well designed, cryonics-appropriate studies to answer these and myriad other questions of great importance.

The problem is, as it has been since the inception of clinical cryonics in 1967, “what, if anything, do we do in the meantime?” Indeed, forty-two years later, we have little direct evidence even that cryoprotective perfusion results in superior conservation of identity-critical information under the real-world conditions encountered by today’s cryopatients than would be the case were they subjected to more timely straight freezing!

Is a patient who has suffered hours of warm ischemia better off simply being rapidly cooled and rendered into the solid state, as opposed to being subjected to 24, 48 or 72 hours of cold ischemia, followed by cryoprotective perfusion and freezing or vitrification? How do we even determine what the ultrastructural condition of a brain is following straight freezing? Freezing in the absence of fairly large amounts of colligative cryoprotectant agent(s) results in the collapse of tissue ultrastructure into dense channels of material, the structural condition of which it is currently not possible to determine by techniques such as transmission electron microscopy. Reaching conclusions based on the post-thaw ultrastructure (or lack thereof) of straight frozen tissue is complicated by the potentially myriad artifacts introduced during rewarming, thawing, fixation and embedding required to image tissue ultrastructure.

Given the extreme resource constraints that have historically been present in cryonics, and the lack of directly applicable mainstream medical research, the answer to the question of ‘what to do’ has been to apply reasoned extrapolation of high quality, peer-reviewed biomedical research to the care of the individual cryonics patient, and where possible, to conduct on-point in-house research to validate such armchair speculation.

It is important to point out that since the inception of cryonics in 1964, until approximately 1976, efforts to establish patient care protocols were a group effort between the then extant cryonics societies. The first of these efforts was organized by Robert Ettinger in 1966 and resulted in the protocol developed by Dante Brunol (8). Beginning in 1972, Fred and Linda Chamberlain, Art Quaife, Greg Fahy, Peter Gouras, M.D., Robert Ettinger, and I engaged in an extensive and largely public effort to reach a consensus about what should constitute a good standard of care for cryonics patients based upon extrapolation (and where feasible) experimental validation of findings in the peer-reviewed biomedical literature. This was done via extensive private correspondence, via publication of findings and recommendations in Manrise Technical Review and The Immortalist, as well as in the form of a detailed procedure manual for administering human cryopreservation entitled Instructions for the Induction of Solid State Hypothermia in Humans published by Fred and Linda Chamberlain and available, in part, on-line at: http://www.lifepact.com/mm/mrm001.htm (Readers interested in obtaining a copy of the full manual, for private use, may contact the author at m2darwin@aol.com).

During the 1980s this effort continued and was both documented and subjected to review by the American Cryonics Society, Trans Time, Alcor and Cryovita Laboratories in the form of detailed technical presentations made at the annual Lake Tahoe Life Extension Conferences hosted by Fred and Linda Chamberlain’s Lake Tahoe Life Extension Festivals from 1979 to 1985[1.] An example of such disclosures is available at: http://www.lifepact.com/tahoe.htm.

In short, these efforts were public, largely collegial, and consisted of a best effort to apply insights from the scientific literature to human cryopatients. Furthermore, both Jerry Leaf and I made a sustained and detailed effort to document, by both presentations and publications, the outcomes achieved in detailed human cryopatient case reports (10-20) and in animal studies of post-cryopreservation ultrastructure, including those designed to reproduce conditions encountered under real-world conditions (21, 22).

These efforts resulted in a number of cryopatient stabilization protocols that incorporated multiple drugs to address the multiple mechanisms of ischemia-reperfusion injury as identified in the literature; an approach which Aschwin describes as administration of “an unorthodox number of medications to protect the brain and prevent impairment of circulation. While there are peer reviewed papers that combine a number of medications, there is no precedent in mainstream medicine or biomedical research in using such a large number of medications (in contemporary cryonics, medications protocol exceeds 12 different drugs and fluids).” This statement deserves further scrutiny.

Are poly-drug approaches to treatment unprecedented in medicine? As an example, let’s consider the case of a hyperkalemic hemodialysis patient who experiences cardiac arrest while preparations are being made for emergency hemodialysis. How many and what kind of medications will this patient likely receive in the setting of refractory cardiac arrest? Per the American Heart Association (AHA) Guidelines the patient will initially receive 1 mg epinephrine IV every 3 to 5 minutes during CPR. This may be substituted (after the first dose) with 40 IU of vasopressin IV. Since the patient is in aystole 1mg atropine IV is also given. Concurrent with the administration of these drugs the patient is given 30,000 IU of sodium heparin to allow for the institution of hemodialysis to definitively reduce the serum potassium level. The patient is given an unsuccessful 360 Joule shock at this point. Point of care evaluation of blood electrolytes discloses blood potassium of 12 mmol/L: a level that is incompatible with the return of spontaneous circulation. A decision is made to administer calcium chloride: 5 mL of 10% solution IV over 2 min and 2 amps (60 mlL) of 50% dextrose in water along with 10 IU regular insulin IV (glucose and insulin facilitate a transient profound cellular uptake of potassium from the interstitial and intravascular spaces). CPR is continued for 8 cycles and the patient is again defibrillated with a resulting non-perfusing rhythm consistent with hyperkalemic cardioplegia. CPR is continued while hemodialysis proceeds. After 4 minutes of hemodialysis a third defibrillation attempt is made with the result being coarse ventricular fibrillation. Following another unsuccessful defibrillation attempt, and confirmation by point of care testing that serum potassium has decreased to 7.8 mmol/L with blood pH at 6.95, 300 mg of amiodarone is given in addition to 1 mEq/kg sodium bicarbonate: by slow IV push; the latter to correct the acidosis that has resulted from prolonged CPR and dialysis with a low pH bicarbonate-acetate dialysate.. Following 5 additional cycles of CPR the patient is successfully defibrillated and recovers with a mild neurological deficit as a consequence of extended, low flow perfusion during CPR.

This patient, undergoing routine resuscitation from hyperkalemia cardiac arrest, has just received 9 discrete drugs, all of them indicated, and all of them within the current guidelines for the treatment of hyperkalemic cardiac arrest (23-24). Interestingly, none of these drugs was administered to ameliorate vital organ ischemia-reperfusion injury. The reason for this is that no such drugs are currently clinically available for this indication.

Similarly, patients undergoing acute fluid resuscitation and initial; treatment for septic shock may receive a dozen or more drugs including pressors, ionotropes, a vasodilator, 2-3 antibiotics, insulin, rAPC, and any ancillary drugs required to facilitate renal replacement therapy or mechanical ventilation (see: http://www.leedspicu.org/Documents/Septic%20shock.pdf). So, it is clearly not the case that, “there is no precedent in mainstream medicine” for a multimodal drug treatment approach to complex illness, since multi-drug interventions constitute the standard of care for resuscitation from both cardiac arrest and septic shock and increasingly serve as the backbone of a wide range of successful cancer chemotherapies.

However, it is the case that, at least until recently, multi-drug interventions in biomedical research to treat cerebral ischemia-reperfusion injury have been virtually nonexistent. This is beginning to change as there is increasing understanding of the complex, multifactorial nature of cerebral ischemia-reperfusion injury. Examples of this are the recent successful work of Buckberg, et al in recovering piglets from 90 minutes of deep hypothermic circulatory arrest using a protocol that employed 5 primary therapeutic drugs (plus leukodepletion using a Leukoguard filter in the arterial line during cardiopulmonary bypass) (25), the work of Liu, et al., demonstrating the effectiveness of a combination of cerebral blood flow promoting drugs and the administration of phenyl-N-tert-butyl-nitrone (a free radical inhibitor) and cyclosporine-A (a mitochondrial poration inhibitor) in improving 24 hour neurological outcome after 8 min of experimental normothermic cardiac arrest in pigs (26) and the work of Gupta, et al., combining melatonin and poly (ADP-ribose) polymerase inhibitors in a rat model of stroke – a study that employed 6 drugs in the most successfully treated group (27).Other research combining multiple drugs and other interventions, such as mild therapeutic hypothermia, have also shown positive results (28, 29).

Aschwin goes on to state, “The only existing justification for using current protocol reflects work done at Critical Care Research (CCR) in the 1990s. Although scattered reports exist about the effectiveness of this protocol in resuscitating dogs from up to 17 minutes of normothermic global ischemia, no detailed (peer reviewed) paper has been published about these experiments “

I do not know what is meant by the term “scattered reports” to describe disclosure of this work and would note that there have been two formal public disclosures, the first in the form of United States Patent 5700828 issued on 12/23/1997, and the second in the form of a public seminar which was subsequently distributed as a videotape: Darwin M, Harris, SB, Russell, SR, O’Farrell, Rasch, C, J, Pengelle, C, Fletcher, M. Routine Resuscitation of Dogs from 15-17 Minutes of Normothermic Ischemia (37.5°C) With Long Term Survival (>6 weeks). In: 21st Century Medicine Seminar on Recent Breakthroughs in Cryobiology and Resuscitation Research, Ontario, CA; 1998.

As the principal investigator on this study, I would be the first to agree that it is both regrettable and unacceptable that it has not been either peer reviewed or published. However, as I do not have access to either the primary or the reduced data from this study, I am personally powerless to remedy this situation. Further, I think it extremely unlikely either that I will be given access to this data, or that the results of this study will be published in any meaningful time frame, if at all, by those at CCR who control the study data.

The question thus arises as to whether the drugs identified in this study are of use, either singly or in combination, in the stabilization of cryonics patients? The only certain way to answer that question is to apply them in well designed animal models that closely approximate the spectrum of real-world conditions under which cryopatients eligible for cardiopulmonary support and pharmacological treatment of ischemia-reperfusion injury present for care. Such studies will take tens of thousands of dollars and several years to complete. So, again, the questions arise, ‘what do we do in the meantime ‘and ‘how do we judge the evidence that we use to justify any interventions we undertake?’

It is not possible to answer these questions without considering the specifics of the work in question. Aschwin states that, “in contemporary cryonics, medications protocol exceeds 12 different drugs and fluids” with the implication that the CCR canine resuscitation series (CRS) research was the source of these 12 drugs/fluids, presumably those described by Aschwin in his January 2007 article Human Cryopreservation Stabilization Medications (http://www.alcor.org/Library/html/stabilizationmeds.html).

In fact, the original CRS protocol included a total of 22 drugs!

o Hemodiluent: defined electrolyte-dextran-40 containing solution
o Hypertensives: 3 primary drugs, 1 secondary drug
o Buffer: tromethamine (THAM), 1 drug
o Antiglycemic: 1 drug
o Free radical inhibitors: 6 drugs
o Excitotoxicity Inhibitors: 3 drugs
o Ca++ Antagonists: 1 drug
o Bradykinin Inhibitor: 1 drug
o Leukotriene Antagonists/Inhibitors: 2 drugs
o COX I&II Inhibitors: 1 drug
o Phospholipase Inhibitor: 1 drug
o Antiplatelet: 1 drug
o PARS Inhibitor: 1 drug
o Metabolic Support: 2 drugs

TOTAL: 22 drugs

Of these, 6 drugs (not including the anticoagulant heparin, the hyperosmotic agent mannitol, the flow promoting agent dextran-40, and the buffer THAM, all of which were previously in use in cryonics) were retained in the protocol licensed by CCR to Alcor and to Suspended Animation, Inc. These drugs are s-methylthiourea (SMT), d-alpha tocopherol (Vitamin E), melatonin, alpha Phenyl t-Butyl Nitrone (PBN), kynurenine, and carprofen. How should the utility of these drugs be judged? The first step in such a process is to determine which patients might benefit based on the available information. By definition, only patients eligible for CPS can be treated, since effective use of all of these drugs requires thorough systemic distribution. Patients with 20 minutes or less of normothermic cardiac arrest are probably the only suitable candidates based on the limited ability of closed chest CPS to generate adequate pressure and flow over increasingly long intervals of cardiac arrest. Beyond this general criterion, it is necessary to consider the evidence for the utility of each drug individually, on the basis not only of the CCR study, but in the context of the published literature.

The patent which first discloses the core drugs used in the CCR protocol was United States Patent 5700828 which was filed on 12/07/1995. This is significant because two of the primary cerebroprotective drugs described in this patent, melatonin and PBN, had not been previously demonstrated to be neuroprotective in cerebral ischemia-reperfusion injury. It was not until 2003 that the first peer-reviewed paper documenting the effectiveness of melatonin in ischemia-reperfusion appeared (30) and not until 1999 that the effectiveness of PBN in cerebral ischemia was documented in the literature (31). Since these papers first appeared a vast literature supporting the effectiveness of melatonin in both focal and global cerebral ischemia-reperfusion injury has appeared, and the PBN analog NXY-059 was demonstrated as effective in a wide range of animal models of cerebral ischemic injury (32)., although the drug failed in a RCT of stroke (33).

The utility of vitamin E, mannitol and of dextran-40 in cerebral ischemia reperfusion injury predate the 1995 patent and are extensively documented in the cerebral resuscitation literature. There are few papers documenting the effectiveness of kynurenine, and no papers supporting the effectiveness of carprofen in cerebral ischemia-reperfusion injury, although there are many papers documenting the utility of other non-steroidal anti-inflammatory and NF-kappa B inhibiting drugs in cerebral resuscitation.

Should any or all of these drugs be applied to cryopatients? Aschwin raises a number of possible contraindications which merit consideration: “The lack of relevant published data to support the administration of large numbers of drugs…in cryonics is not just a matter of risking performing redundant procedures. A lot of time and resources are being spent in cryonics on obtaining and maintaining equipment and supplies for these procedures, in addition to the licensing fees paid to use some of these technologies and the training and recruiting of people to perform them. But perhaps the most troublesome problem is that the preparation and execution of these procedures during actual cryonics cases can seriously interfere with rapid and effective cardiopulmonary support and induction of hypothermia.”

It is clear from the foregoing that Aschwin considers immediate post arrest cooling in the presence of CPS to be an essential element of effective cryopatient stabilization. Unfortunately, the use of CPS in this setting carries with it the risks of return of consciousness (33) as well as the return of ‘signs of life’ such as agonal gasping (34, 35), spontaneous movement (36, 37) and even the return of spontaneous circulation. (38). This implies that the cryopatient undergoing CPS must be protected against these undesirable effects by pharmacological intervention. At a minimum, this means that intravenous (IV) or intraosseous (IO) vascular access must be established and at least 3 drugs must be administered (e.g., an anesthetic, a paralytic, and a cardioplegic). Thus, much of the skill, equipment and added personnel required to administer cerebroprotective drugs to cryopatients are, in fact, a requirement of delivering CPS assisted cooling. When Aschwin writes: “the preparation and execution of these procedures during actual cryonics cases can seriously interfere with rapid and effective cardiopulmonary support and induction of hypothermia” it is not clear what he means? Is it establishing IV or IO access, or the administration of a large number of drugs, or both that constitutes a threat to rapid post-arrest CPS and cooling?

CPS and vascular access must, necessarily, proceed together, with CPS (properly) trumping vascular access where any conflict occurs. It should also be noted that CPS, given in the absence of an effective pressor, and (in most cryopatients) volume expansion, will not achieve perfusion that is effective; either for supplying adequate cerebral blood flow to prevent ongoing ischemic injury, or to facilitate heat exchange. CPS implies not only vascular access and the attendant skills, complexity and hardware, but also the administration of at least half a dozen drugs in order to render it both safe and effective. Given this requirement, what are the additional burdens and costs of delivering cerebroprotective medication?

Currently, melatonin, PBN, vitamin E, and carprofen are combined into a single parenteral product by CCR (Vital-Oxy) which can be administered IV or IO via a stopcock manifold using a pressure infuser. Heparin (anticoagulant), vercuronium (paralytic), magnesium sulfate (cardioplegic) and the first dose of vasopressin (pressor) can similarly be combined to create a single parenteral product shortly before use and may be administered ‘push’ via the stopcock manifold. Dexrtran-40 and mannitol may also be combined into a single parenteral product with a total volume of ~550 mL which can also be given via pressure infuser and the stopcock manifold. Bolus, or continuous doses of vasopressin and THAM (buffer), can be given via the same stopcock manifold using battery operated infusion or syringe pumps.

The broader issue to be addressed is how these multiple medications may be given rapidly, accurately, and with the least use of personnel. Compact, battery operated infusion pumps for in-field use are now available, but they cost a fortune. The same is true of programmable, battery operated syringe pumps. I think the solution to this problem is to computerize it. A laptop computer should already be in use during cryopatient stabilization and transport to acquire data from the patient and it can and should be used to give the meds as well. One simple system for doing this would be to use pressure infusers, and syringes under pressure, with open/close line-clamp solenoids under computer control. Meds would be dispensed by the interval of solenoid opening; push meds would be a full open solenoid, and interval bolus meds would be given by briefly, and for a fixed time, opening the solenoid(s). This is an extremely simple system to implement from both the hardware and software standpoints. A schematic of this type of system is shown below:

darwin_meds

Of course, this presumes that the multidrug approach to cerebroprotection of the cryopatient is economically justified. I would be the first to agree that it is not necessary to pay costly licensing fees to derive most of the benefit from the CRS protocol. It is clear from reviewing the literature that the most widely validated and likely most potent drugs in this protocol (in the context of preventing ultrastructural injury secondary to ischemia-reperfusion injury) are melatonin, PBN[2], and, arguably, vitamin E. These are readily available molecules and may be used by any cryonics organization, absent licensing, on the basis of their documented protective effects in the literature. Other likely useful drugs such as dextran-40, THAM and mannitol have a long history of use in cryonics which predates the CCR research and these drugs may also be used at little cost (Darwin M. Transport Protocol for Cryonic Suspension of Humans, Fourth Edition. 1990, http://www.alcor.org/Library/html/1990manual.html).

In the nearly decade and a half that have elapsed since the CCR canine resuscitation series was undertaken many other promising experimental drugs for the inhibition or moderation of cerebral ischemia-reperfusion injury have emerged. I am in complete agreement with Aschwin that the best way to evaluate the potential utility of these drugs to cryopatients is in animal models that are truly relevant and which simulate the actual condition of cryonics patients who present for stabilization and transport. Such patients are typically suffering from extensive activation of the immune-inflammatory cascade, are often severely dehydrated or fluid overloaded, and invariably suffer from serious disturbances in cerebral microcirculation which begin hours or even days before medico-legal death is pronounced. As a consequence, these patients will typically have pre-arrest ischemic injury which will likely be compounded by post-arrest reperfusion. Evaluation of pharmacological interventions should, and indeed properly must be, carried out in animals models that reflect these facts.

Finally, Aschwin writes: “Even more complexity is introduced when cryonics organizations make an attempt to wash out the blood and substitute it with a universal organ preservation solution. The rationale for this procedure is found in conventional organ preservation and emergency medicine research. The question in organ preservation research is no longer whether hypothermic organs benefit from blood substitution with a synthetic solution, but what the ideal composition of such a solution should be. In emergency medicine research asanguineous hypothermic circulatory arrest is increasingly being investigated to stabilize trauma victims. But it is a major step from these developments to the practice of remote blood washout of ischemic patients with expected transport times of 24 hours or more. At present the only sure benefit of remote blood washout is that it enables more rapid cooling of the patient, a benefit that should not be underestimated. But when liquid ventilation becomes available to cryonics patients, rapid cooling rates will be possible without extracorporeal circulation.”

There can be no argument that blood washout followed by long delays to cryoprotective perfusion is deleterious (as currently practiced) on the basis of both clinical experience with cryopatients and recent unpublished animal research by Fahy, et al., of 21st Century Medicine (39). This practice should probably be abandoned until such time as effective solutions are developed for use in cryopatient transports. The statement that “when liquid ventilation becomes available to cryonics patients, rapid cooling rates will be possible without extracorporeal circulation,” is by no means assured. As the primary inventor of fractional tidal liquid assisted pulmonary cooling (40), I feel it is critical to point out that this technique has been validated only in the setting of healthy animals with spontaneous circulation. The reduced flow state attending external CPS and the typically severely injured lungs of the cryopatient present the twin challenges of greatly reduced blood flow coupled with greatly reduced pulmonary surface area (as a consequence of pre-existing or emergent lung injury; i.e., acute respiratory distress syndrome or acute lung injury resulting from closed chest CPS). which will dramatically reduce the efficacy of heat exchange achievable with this technique.

Once again, as Aschwin correctly notes in the context of pharmacological intervention, it is imperative that modalities developed for application in conventional clinical medicine be validated in the very different setting of the patient presenting for cryopreservation after succumbing to prolonged terminal illness – as well as the added insults of peri- and post-arrest systemic and cerebral ischemia.

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31. Shuaib A, Lees KR, Lyden P, Grotta J, Davalos A, Davis SM, Diener HC, Ashwood T,Wasiewski WW, Emeribe U; NXY-059 for the treatment of acute ischemic stroke, N Engl J Med. 2007 Aug 9;357(6):562-71.
32. Siesjö BK, Elmer E, Janelidze S, Keep M, Kristian T, Ouyang,YB et al. Role and mechanisms of secondary mitochondrial failure. Acta Neurochir (Suppl) 1999: 73: 7–13.
33. Darwin, MG, Leaf, JD, Hixon, H, Neuropreservation of Alcor Patient A-1068. http://www.alcor.org/Library/html/casereport8504.html#part2
34. Clark J, Larsen, MP, Culley, LL, Graves, JR, Eisenberg, MS. Incidence of agonal respirations in sudden cardiac arrest. Ann Emerg Med 1992;21(12):1464-7.
35. Rea TD. Agonal respirations during cardiac arrest. Curr Opin Crit Care 2005;11(3):188-91.
36. Jain S, DeGeorgia, M. Brain death-associated reflexes and automatisms. Neurocrit Care 2005;3(2):122-6.
37. Maurino, SJ, Saizar, R,.Bueri.J, Frequency of spinal reflex movements in brain-dead patients. The American Journal of Medicine, 2004, 118(3):311-314;36.
38. Vukmir R, Bircher, N, Radovsky, A, Safar, P. Sodium bicarbonate may improve outcome in dogs with brief or prolonged cardiac arrest. Crit Care Med 1995;23:515-22.
39. Fahy, GM The Whole-Body Vitrification Project at 21st Century Medicine. In the Suspended Animation conference held in Fort Lauderdale, Florida, from May 18th through May 20th May 2007.
40. Federowicz (Darwin), MG, Russell, SR, Harris, SB, Mixed-mode liquid ventilation gas and heat exchange. United States Patent 6,694,977, published 24 February, 2004, http://www.freepatentsonline.com/6694977.html.

ENDNOTES:

[1] The Cryonics Institute declined repeated invitations to participate in these colloquiums.
[2] It is important to note that the PBN used in the CCR study was prepared by dissolving it in boiling water with concurrent microwave heating in the presence of atmospheric oxygen. This is very likely significant because such handling would inevitably create breakdown products of PBN, such as NtBHA and its oxidation product the spin-trap MNP. As Proctor, et al., have pointed out, (Peter H. Proctor and Lynsey P. Tamborello, SAINT-I Worked, But the Neuroprotectant Is Not NXY-059, Stroke 2007 38:e109; published online before print August 23 2007.) it is possible that the failure of NXY-059 in the SAINT-II trial was due to the fact that material used in this trial differed from that used in the successful SAINT-I trial in that it was stabilized and protected against oxidation. It may well be that it is not PBN, per se, that is cerebroprotective, but rather its oxidation and/or break-down products.

Marcelon Johnson dies and is not cryopreserved

For Immediate Release, Friday, 24 January, 2009

Date: 23 January, 2009

Introduction

I have been informed that Marcelon (Marce) Johnson died on 01/21/2009, was cremated, and not cryopreserved.

I understand this information may come as a surprise and as a disturbing shock to many people, especially those who loved and knew Marce, as I did. I thus feel an obligation to explain how this happened and to provide some closure to this story for the many people who helped, or tried to help, avert this catastrophe.

While Marce was alive I was unable to share the full story of what was happening. Now that she is dead and gone I believe it important and the responsible thing to do to relate the story as best I know it.

I do not have access to my records here, so dates precise dates will be missing or supplied later in an amended account (if there is any interest).

A Brief History

Early in January of 1964 a 35-year-old Huntington Beach, California housewife named Marcelon Johnson finished filling out her cryonics paperwork, paid her first cryonic society dues, and dropped her application for a Medic-Alert bracelet in the mail. She had six children and a busy, happy, life which has just gotten better because she now believed, for the first time, that she might never have to die. She had been haunted by the death of her mother who was in her mid-50s when she succumbed to Alzheimers disease. She did not want to die that way, or any other way, for that matter.

Within a year Marcelon Johnson, or Marce as was known to her friends, would become increasingly involved in cryonics. By March of 1967, 3 months after Dr. Bedford began the journey which he continues to this day, Marce Johnson was the Secretary-Treasurer of the Cryonics Society of California (CSC). She opened her home to cryonics meetings and catered them superbly. She answered countless information requests and filled countless orders for books and literature. On October 11, 1974 Marce reluctantly accepted the Presidency of CSC, not suspecting that she had stepped into a nightmare that would go on for almost eight years. Russ Stanley, who had welcomed Marce to her first cryonics meeting on September 30th in 1966, had been frozen (or so it seemed) for 6 years. Two of the other pioneering CSC members whom she had met and befriended were also (presumed) in cryonic suspension at CSCs Cryonic Interment Facility in Chatsworth, CA.

In the 45 years was actively involved in cryonics I have never heard anyone say a bad thing about Marce Johnson. That was an extraordinary achievement for anyone involved in cryonics, but it was made all the more extraordinary by the fact that Marce was the de facto President of CSC when it came to light in 1979 that all of the patients in the Chatsworth facility had been allowed to thaw and decompose. No, Marce had no complicity in that horror beyond that of being loyal and trusting. The very qualities that made Marce an exceptional human beig: her readiness to help, her willingness to trust the words of a friend and colleague, and her quiet and nearly unshakeable loyalty had set her up to be in the crosshairs of the litigation and enmity that followed.

The very public disintegration of CSC was not only financially costly to Marce and her husband Walt (not to mention their 6 children), it was a deep personal humiliation and loss. Three of the people who had welcomed her into cryonics were now gone lost to a gruesome and disgraceful fate. There was no immortality for them; in fact, there was not even the dignity of a decent burial. Many of the people who were cohorts of Marce at that time walked away from cryonics and never looked back and most of them are dead now, or are beyond help in nursing homes, or dependent upon their indifferent children. I have watched as those who died passed, and I have spoken with those who remain, helpless and dying. Chatsworth was not a pretty business.

Marce Johnson did not walk away. She joined Alcor, and at a very bad time for Alcor in 1981. Over the next ten years Marce hosted more Alcor meetings than anyone else has before or since. She and her husband Walt were a dependable source of contributions, and Marce would often make the 2 hour drive (each way) from Huntington Beach to Fullerton to help with various volunteer activities at Alcor. Her gentle, intellectual decency served as a welcome beacon of normality and warmth at cryonics get-togethers that were often marred by partisanship and extremes. Marces home was one of the least conveniently located in Southern California, but the meetings she hosted there were among the best attended.

In 1985 Alcor faced a seemingly insurmountable crisis. For 7 years Alcor had been the guest of Cryovita Laboratories in Fullerton, California. Cryovita was the creation of cryonics pioneer Jerry Leaf and it was a costly drain on Jerry and his family. Jerry not only paid the rent on the facility in Fullerton, he covered all the other operating expenses out of his pocket, including the liability insurance required by the landlord. In the early 1980s the explosion of litigation in California and elsewhere resulted in skyrocketing premiums for basic business liability coverage. By 1985 coverage at any price was no longer available for businesses with a high, or impossible to estimate degree of risk. Alcor, and thus Cryovita, became uninsurable and with that came the inevitable edict from the landlord to vacate the premises.

With the help of a long-time friend of Alcor, Reg Thatcher, a potential solution was identified. A small park of industrial buildings was going to be built in nearby Riverside, California with completion expected in about 10 months. We negotiated with the landlord and began trying to raise the impossible sum of $150,000 plus closing and other costs. We had from April 4th to June 20th, 1986 to do just that a little over two months. At $149,000 we stalled out. All the deep pockets had been tapped and the Life Extension Foundation was locked in a battle with the FDA for its survival, as well as for the personal freedom of Saul Kent and Bill Falloon, both of whom faced decades in prison. Alcor had approximately 100 members in 1986, and finding the additional $5,000 in cash required to cover the closing costs appeared hopeless. As it was, an additional $37,500 had already been pledged to cover the 2-year note carried by the developer. When Marce heard of this situation she quietly opened her and Walts check book and wrote out a check for $5,000.

In the years that followed, Marce was always there for cryonics and it wasnt easy. She and Walt had had to buy life insurance late in life and the premiums were punishing, even for neuro. Sometime around 1997 Marce asked me to meet her for lunch in Huntington Beach. That was an unusual request, but one which I was happy to oblige. It was an unexpectedly emotional and difficult meeting. As we sat in a little Italian restaurant in an anonymous strip mall Marce repeated the story of her mothers death and asked me to promise that I would not abandon her should such a fate befall her. She told me a number of deeply personal things and she asked me to dispose of some unfinished business should I outlive her. It was easy to say yes. Marce was healthy and had every prospect of living many years longer in good health. It takes extraordinary courage to confront not only your own mortality, but also the prospect of closing your life in the darkness of dementia. Nothing in my experience of Marce as a relentlessly positive and optimistic person had prepared me for that meeting.

In 2001 I was alerted by Joan OFarrel of Critical Care Research that Marce seemed both forgetful and inappropriate on the phone (Marce was, as usual, doing volunteer work, this time for Critical Care Research (CCR) and 21st Century Medicine). A call to Walt confirmed Joans suspicions and shortly thereafter Dr. Steve Harris and I visited Marce. Steve did a thorough exam, including an assessment for Alzheimers. Marce did well on this assessment, but Steve suggested she go to the Memory Clinic at UCLA for a more comprehensive evaluation. I tried to call Walt and Marce over the following 2 years and always ended up getting Marces voice on their answering machine. Finally, in 2003 Walt picked up the phone and we talked. I learned that Marce had been placed in a nursing home some months prior, and that she had moderately advanced Alzheimers.

That news was devastating enough, but what followed shook me to the core of my being. Walt told me that Marce no longer had cryonics arrangements and that she was to be cremated. I visited Marce twice in the subsequent months and found her still oriented enough to recognize me and carry on a very basic conversation. From these two visits I learned that Marce still believed she was going to be cryopreserved and that she felt that she had done something wrong, perhaps by getting sick, which had caused her cryonics friends to stop coming to see her. I learned that Saul Kent had been down to see her and Walt and to try to get Walt to reinstate Marces arrangements, but to no avail. Walt had never been a cryonicist and his concern was, understandably, with ensuring that Marce got top quality nursing home care. Walt and Marce were confronted with spend down in the face of monthly nursing home bills of over $5,000. Medicare does not begin to cover these expenses until the patient has $2,000 or less in total assets not even enough for burial. Marces and Walts cryonics insurance policies had been cashed-out and used for her nursing home care.

In the six years that have come and gone since then a number of people have continued to try to find some way to rescue Marce from this situation. Marce did everything right, everything that cryonics organizations asked her to do, including giving them ownership of her policy. Unfortunately, Marce fell ill just as CryoCare was closing down and she never had the opportunity to transfer her arrangements to the Cryonics Institute, or Alcor.

Dave Pizer of the Venturists stepped forward to organize a fund raising effort for Marce. Dave believed, as I did, that the primary obstacle to getting Marce cryopreservation arrangements was money, not any unwillingness on Walts part. days ago Walt confirmed this by consenting to have Marce cryopreserved at CI when the time comes. CI graciously agreed to accept Marce as a member and her future now rests on the ability of the Venturists to raise the $35,000 required to cover CIs costs and to transport Marce to CI from Southern California.

The Rest of the Story

Unfortunately, shortly after the appeal for Marce detailed above was launched, Walt retracted his offer of cooperation and support. When Walt and I spoke about the efforts on Marces behalf he was warm, gracious, and cooperative. Because of the criticality of the matter (Marces potential life or death) I did something I have done only a few times in my adult life: I recorded the conversation between Walt and I without his knowledge. This was a legally permissible action since the call (on my end) was made in Arizona, which has no law prohibiting such recording. When I subsequently called Walt (about 2-weeks later) to set up arrangements for him to sign the CI paperwork in the presence of a notary (Walt had suggested that we do this at his bank, a branch of which was located just around the corner form his home) Walt stated he had changed his mind and that he had decided that Marce should not be cryopreserved and instead would be cremated, in keeping with his, and the rest of her familys wishes. To say that I was both stunned and unprepared for this turn events was an understatement. When I asked to meet with Walt and other concerned members of the family, Walt said that, he had said all he had to say and hung up on me.

After lengthily consultation with Saul Kent, Dave Pizer, and a prominent scientist and cryonicist close to Marce and Walt (including playing the tape recording of the conversation between Walt and I), a decision was made to do the following things:

1) Attempt to arrange a meeting with Walt between Saul Kent and the cryonicist/scientist who had known Marce and Walt since his teenage years in Southern California and who could argue both scientifically, and on the basis of personal knowledge, that cryopreservation was warranted in Marces case and in her condition of advanced Alzheimers disease.

2) Contact Marces most influential (and sympathetic to cryonics) daughter and speak with her in detail about the situation and, if possible, enlist her support in the effort to change Walts decision.

3) No attempt would be made to use the court system or other legal coercive mechanisms to challenge Walts or the familys decision in this matter. Since both Marces husband, her many children, and her other relatives were not supportive of cryonics or were opposed, it was deemed by Saul Kent, and Dave Pizer, that litigation would prove not only fruitless, but possibly counterproductive.

4) Considerations in making the decision not to take coercive action(s) were that Walt was himself dying (he is currently in hospice care) raising the possibility that he might not outlive Marce opening another opportunity to revisit the matter with her children. Other considerations were that there was no funding for such an effort and approaches to several attorneys who might work pro bono (or provide advice gratis), yielded no offers of help and the uniform opinion that litigation would be unsuccessful and costly. [ It probably also should be noted that one similar such effort in the past proved a financially costly failure.]

Saul Kent argued that public disclosure of this turn of events would damage the fundraising effort for Marce and that the most conservative course of action was to proceed with efforts to rescue her until all hope was gone; in other words until she was dead and disposition was completed. Most involved agreed that this was the most conservative course of action to pursue.

This sad outcome has now been realized.

My own heartbreak knowns no words, and although I expected this outcome for many months, it is still difficult to bear.

Marce lived her life without bitterness or anger, and with malice towards none. Those who knew her will understand this and will hopefully also understand that I honor her here by saying simply that I will miss her and that, as is the case with so many others Ive loved and lost, I will neither forget, nor stop looking for ways, however remote in possibility or in time, to somehow recover her.

Information for Contributors

For those who contributed to the effort to help Marce, please contact the Society for Venturism c/o Dave Pizer: pizerdavid@yahoo.com or at:

The Venturists

C/O The Creekside Lodge

11255 State Route 69

Mayer Arizona 86333

for information on how to obtain a refund of your contribution, or to reassign it for use by Bill O’Right’s.

Cryonics sets example for emergency medicine

One of the most neglected aspects of cryonics is that its procedures, and the research to support them, can have important practical applications in mainstream fields such as organ preservation and emergency medicine. Contrary to popular opinion, cryonics does not just involve an optimistic extrapolation of existing science but can set the standard for these disciplines. As a matter of fact, that is exactly what cryonics, and cryonics associated research, has been doing over the last 25 years.

The most striking example is the progress in vitrification as an alternative for conventional cryopreservation. Although the idea of eliminating ice formation at low subzero temperatures has been discussed since the beginning of cryobiology, vitrification as a serious research agenda was largely driven by the demand for ice-free preservation of the human brain. Over the last decades this research has culminated in the development of the least toxic vitrification agent to date, 21st Century Medicine’s M22.

The contributions of cryonics to mainstream science and medical practice are not confined to cryobiology. Researchers Jerry Leaf and Mike Darwin made impressive progress in the formulation of bloodless whole body organ preservation solutions to resuscitate dogs from ultraprofound hypothermic temperatures, an intervention that is increasingly being recognized as essential to stabilize trauma victims. In the mid 1990s, Mike Darwin and Steve Harris conceived and developed the idea of using liquid breathing with perfluorocarbons as a method to induce rapid hypothermia. They further validated a multi-modal medications protocol to resuscitate dogs from up to 17 minutes of normothermic cardiac arrest without neurological damage.

Although progress has slowed considerably in the non-cryobiology research areas over the last 10 years, it is encouraging to observe that some of the procedures that are routine in cryonics  stabilization protocol  are starting to catch on in mainstream emergency medicine practice as well. For example, contemporary cryonics stabilization protocol has been strongly shaped by the idea that the best strategy to limit brain injury after cardiac arrest is to combine a number of different interventions: cardiopulmonary support, induction of hypothermia, and administration of circulation-supporting and neuroprotective medications.

It is therefore very encouraging to learn that the Wake County EMS group in North Carolina has achieved impressive results in treating out-of-hospital cardiac arrest victims using a protocol that closely follows elements of current cryonics stabilization protocol. Systematic implementation of immediate induction of hypothermia, continuous compression CPR, and the use of an impedance threshold device (ResQPOD) produced an almost 400% improvement in survival and vast improvements in neurological outcome. A PowerPoint presentation about their experience and protocols are available at their website.

Such real world outcomes do not only inspire confidence in the procedures cryonics organizations can use to protect patients from brain damage after cardiac arrest, it should also serve as a wake-up call to relaunch an aggressive research agenda to push the limits of hypothermic and normothermic resuscitation. In absence of this, it will only be a matter of time before cryonics activists can no longer claim that “we did it first.”

HT Mike Darwin

Refractometry in cryonics

Contrary to popular opinion, in cryonics the blood of the patient is replaced with a cryoprotective agent to reduce freezing, or more recently, to eliminate ice formation altogether through vitrification. This procedure requires surgical access to the circulatory system of the patient to wash out the blood and replace it with a cryoprotective agent. But how do we know what the concentration of the cryoprotective agent is in the brain of the patient?

There are a number of methods to estimate the concentration of the cryoprotective agent including specific gravity (SG) and freezing point depression osmometry. Such methods can be impractical and time consuming. In the following article from Long Life Magazine (1978), Mike Darwin introduced refractometry as a method to determine cryoprotective agent concentration. Measuring the refractive index of the perfusate to estimate the concentration of the cryoprotectant in the patient is still practiced in cryonics today by taking samples of the arterial, venous, and burr hole effluent.

The sort of handheld refractometer that is discussed in Darwin’s article was used by Alcor  for manual refractometry measurements until the  organization obtained a benchtop refractometer in the mid-2000’s.  Alcor also collects continuous refractive index measurements using LabView and in-line industrial refractometers.  In 2007, Aschwin de Wolf  recommended the Reichert AR2000, a digital handheld refractometer, which is convenient to use, offers a wide reading range and a choice of different scales, and can be used with software to automatically record data.  The Reichert AR2000 is currently used by the Cryonics Institute.

Mike Darwin – Refractometric Determination of Cryoprotective Agent Concentration PDF

Time for the rebirth of cryonics in Britain

A PDF file of this article with images is available here.

“Tenderly you stroke a Nettle, and it stings you for your pains. Grasp it like a man of mettle, and it soft as silk remains.” – Old English proverb

Nearly 20 years ago Alan Sinclair successfully undertook to establish a cryonics facility in the UK. The Alcor UK facility in Eastbourne was a superb facility which, at that time, was far superior to the facilities Alcor then occupied in the U.S. The Eastbourne facility opened in 1990 and culminated efforts which had begun only 4 years before to establish a cryonics beachhead in the UK.  I have intimate knowledge of these efforts because I was instrumental in facilitating them.  The nucleus of the Alcor UK group consisted of Garret Smyth, Mike Price, Max More (née Max O’Connor) and Luigi Warren.  These four young men joined Alcor as suspension members and began working towards promoting cryonics in Britain with an eye towards positioning Alcor UK as the regional service provider for Western Europe as well as the rest of the UK.  A least to me, the Eastbourne facility seemed the enabling event that would make that dream a reality. The major reason Alan gave at the time for providing the initial funding for the facility was his desire to have quality cryopreservation services for himself and his family; something that was unarguably not possible absent both a facility and an organization of committed and competent people to perform cryopreservations.

Unfortunately, not only didn’t the dream of a solid and enduring cryonics beachhead in the UK and Europe materialize, the Alcor UK facility itself “vanished” into the sands of time.  Now, 18+ years later, Alan is on the same quest, but far from making progress, finds himself in the sorry position of telling British cryonicists “we will have a straight freeze in the UK.” As I sit here in London writing these words I feel a mixture of disbelief and horror at the way things have turned out for UK cryonics. How did things go so wrong and is there anything that can be done to remedy the situation?

To answer the first part of that question it is necessary to understand the paradigm that was in play in the late 1980s when cryonics was taking shape in Britain with the founding of Mizar. Certainly, Garret Smyth and I had a clear vision of how cryonics in the UK should be pursued and that vision was that the UK cryonics group becomes functionally autonomous and capable of delivering the full range of services including long-term cryogenic storage.  This may seem strange given that storage was a “mature” technology in the US and was just starting to experience substantial economic benefit from the economies of scale which come from having more than a handful of patients, principally lower costs for custodial labor, liquid nitrogen (which drops in price dramatically with larger quantity purchases),  per-patient back-up dewar costs (one back-up dewar is needed whether there is 1 patient in storage or 50 patients), and of course lower per-patient floor-space charges. Given these tough economic realities why try to do storage outside of the US?

The most powerful answers to this question are the least obvious and the most indirect. More than any other thing, caring for patients in storage acts to both validate and stabilize a cryonics organization.  Storage being undertaken “close to home,” without the enormous financial, logistic, and psychological barrier of UK patients being cared for half-a-world away in another country, creates a powerful sense of immediacy and reality, especially for the relatives of patients getting cryogenic care.  It dramatically decreases the sense of unreality and otherworldliness that attaches itself to patients being sent to the US which is not only geographically distant, but culturally distant as well.

Aside from these psychosocial advantages local storage has the advantages of generating sustained, and above all serious, media coverage for cryonics in both the UK and Europe. It validates cryonics as a British (and potentially as a European) undertaking as opposed to some “alien” activity centered in the US – where most of the Homo sapiens varieties of nuts and fruits were presumed to have migrated long ago. Even more practically (and more selfishly from my perspective as the President of Alcor at that time), a UK storage capability would constitute a lifeboat, a safe haven to which US cryopatients could be transferred in the event storage operations in the US became problematic or impossible. Redundancy and diversification are, if anything, more important in cryonics than they are in prudent investing. The UK held the promise as the place where a reliable, respectable, and fully independent cryonics operation could take shape.

I consider Alan Sinclair a good and dear friend. He and his wife Sylvia have extended enormous hospitality and kindness to me at times of extreme need. For this, and for his tireless actions on behalf of cryonics, I am and I will remain forever grateful. However, as is the case with most of us who have pioneered cryonics, Alan has made his share of mistakes. (Having made far more than my own share of mistakes I am in a good position to sympathize.) By far the most serious of these mistakes was Alan’s unrelenting opposition to cryopatient storage in the UK. Since Alan had initially provided virtually all of the funds for the Eastbourne facility his position on this matter became the de facto policy for cryonics in Britain and thus, indirectly, for cryonics in all of Western Europe.  While few patients were cryopreserved in the UK, this was not the case for Western Europe or for the Near East, and a steady stream of patients either relocated to the US when terminal (invariably at great personal financial expense and often at the cost of psychological torment for themselves and their loved ones). Patients who arrested in Europe and Russia suffered grievous ischemic insults (both cold and warm); no patient reached the US for cryoprotective perfusion in less than 24-hours and most have suffered delays of 48 hours and in some cases of 5 days!

In 2001 Alan moved that the Eastbourne facility be sold and this is exactly what happened. A short while later Alan changed his mind about the wisdom of this move and purchased another building in what proved to be an unsuccessful attempt to open a replacement UK facility. Late in 2003 Alan announced that he believed the Cryonics Institute (CI) offered superior services for vastly less money and he joined CI as both a suspension member and as a member of CI’s Board of Directors.  Early in 2006 Alan left CI to re-join Alcor because, as he stated at the time, “Alcor will be offering whole body vitrification in the near future.” Now, less than 2 years later, he writes (sic):

“I am always asked who uk members should have as there service provider, I am always very reluctant because the whole issue is very complicated and I do my best to keep impartial but I can say without the ability to transport at -196 we can forget vitrification from Alcor they have said we will have a straight freeze in the UK, CI seem to be better so those who were thinking of changing think again.”

I know for a fact that these changes in direction have been financially and emotionally costly for both Alan and his wife Sylvia. What is perhaps a less appreciated fact is that these abrupt alterations in course have repeatedly whipsawed the UK cryonics community causing confusion, fragmentation, and no small measure of hard feelings.  A number of good quality people with a long history of commitment and activism in British cryonics have walked away in disgust and are now deeply alienated and burned out. As my recent travels have demonstrated (at least to me), a far worse result has been the failure of UK cryonics to attract the next wave of recruits and to make their message in any way appealing to or relevant for young people – the people who must necessarily be attracted to provide not only new ideas and new energy, but also to provide the continuity of care required to carry existing cryonics members and patients into the future for rescue.

Cryonicists in Europe and in Russia have reacted to the moribund and lifeless state of cryonics in Britain by doing (wisely) what they must in order to survive: strike out on their own and reinvent the wheel.  In particular, in Russia, they have taken the extraordinary step of storing their own patients at great cost and hardship and now, in less than 2-years from the start of their efforts, there are 5 patients in liquid nitrogen storage in Russia. This is not to imply that this is a good situation; in many ways things have begun to play out as they did for cryonics in the late 1960s in the US (read Arlene Sheskin’s excellent analysis: Cryonics: A Sociology of Death and Bereavement for the sorry details).  While there is great risk for cryonics in Russia there is also great reason for optimism. However, the point is that things needn’t have turned out the way they have and the European and Russian cryopatients and their respective communities needn’t have suffered as they have.

Beyond the harm these people have suffered due to lack of a viable, full-service cryonics capability in the UK and Western Europe, there is the unquestionably far greater harm that has befallen the people who did not get cryopreserved at all because they didn’t sign up, or their families chose not to take action because of the substantial logistic hurdles, long ischemic intervals, and psychological distance that were and are the consequence of US-only cryonics.  During my past few months here in Britain I have met quite a number of bright, motivated and often highly professional people who have specifically not made cryonics arrangements because it is their perception that absent high quality and comprehensive local services they would be wasting their money. While it can certainly be argued that this is specious reasoning given the alternative, and that the best is ever the enemy of the good, the fact remains that this is the case and this is a major barrier to recruitment and growth for cryonics outside of the US.

Undoubtedly, one reason this is so is because of technological advances that have been occurring both inside and outside of cryonics. The forward march of stem cell, cloning and regenerative medicine technologies have acted to make cryonics more credible to the serious, knowledgeable professional. At the same time, the vastly improved preservation which is theoretically (though not yet practically) available as a result of advances in cryoprotection (i.e., vitrification or near vitrification of the brain) have made cryonics more credible by divorcing it from the need for super-sophisticated, highly theoretical and wholly unproved nanotechnology.  I have had extensive conversations with several medical professionals active in Transhumanist and related forward-looking communities here in London and I have repeatedly heard the same message: “Not only would I sign up for cryonics, I would actually be professionally involved, but only if there were services here in the UK and only if these services were of a high quality and at least offered the opportunity for people who “die” under good circumstances to get excellent treatment.”

To a great extent this change in attitude and the accompanying potential to recruit a new class of cryonicist has been due the work of the Transhumanists and to Aubrey de Grey and the potent nucleus of superbly educated, talented, highly motivated, and (perhaps most importantly) young people he has attracted and assembled with the Methuselah Foundation and his SENS program.  These people (and many others like them yet to be recruited) are focused on progress and technological excellence. They are professionals in their own disciplines and they are not interested in a cryonics service which has the stench of days-long ischemic intervals and very suboptimum cryoprotection associated with it. There is the clear potential for the rebirth of a vigorous, technically competent and above all autonomous cryonics movement in the UK (and by extension in Western Europe as well).  The success or failure of such an effort hinges on the people involved realizing that cryonics is first and foremost their problem and that no one in the US (or anywhere else), no matter how well intentioned, can solve it for them.  American cryonics organizations are thousands of miles away and their members and staff live and work in a different world; it is unrealistic and unfair to expect them to be able to appreciate the unique problems of UK and Western European cryonicists. (And by the same token, Russian cryonicists cannot expect European Union cryonics, should it develop, to meet their needs given the vast linguistic, cultural, legal, and geographical hurdles unique to their situation: they are right to pursue their own program at this point in time.)

The sane and solid understanding of the people who launched the cryonics societies was that even within the US, the development of local groups with substantial autonomy to act in their own best interests based on their unique local circumstances, was of the utmost  importance. Indeed, the imperative for local groups and ultimately for regional full-service cryonics facilities was the raison d’être for the creation of the Cryonics Society of New York and the Cryonics Societies of America and was the proximate cause of the split from the Life Extension Society (LES) and thus, ultimately, LES’s demise. In the case of nation-states with different laws and different cultures it was presumed from the beginning that the needs of their cryonicists could only be met by those selfsame cryonicists.

In hindsight, it has become clear that the critical error that was made by those of us in the US who had made cryonics our full-time vocation, indeed our profession, was to treat well intentioned and highly motivated individuals like Alan Sinclair as colleagues instead of as customers. That was a devastating error for which I must assume my share of responsibility. There have been a few cryonics professionals and I am proud to count myself among them. In failing to both realize and assert this fact, those of us who have become professionals in this field have done a great disservice to ourselves and to the cryonics community at large.

Patients are not well served by practicing medicine on themselves and if a doctor is a fool who has himself for a patient, then how much more a fool is a patient who has himself for brain surgeon, or vastly much worse as a cryonics patient? In all fairness and honesty, cryonicists had no choice in this matter early on and, depending upon their location and resources, many will have little choice for years to come. Absent competent scientific, technical and medical support we have had no alternative but to be not only our own physicians, but also all too often our own lawyers, accountants, industrial designers, equipment fabricators, and even cryogenic engineers. In the absence of broad support from the professional communities (or large amounts of money to buy it) it was, literally, do or die (and in many areas of the world remains so to this day).

When a serious effort to create a cryonics capability in England began 1986 the situation was somewhat different from what it was from 1964 to 1984 in the US. By that time there were full-time professionals doing cryonics and there were well established and documented procedures and protocols for administering the treatment.  Twenty years of effort had gone before and had resulted in workable solutions to problems in most of the administrative and technical areas of cryonics. Sound, medically based models of perfusion using reasonably safe equipment were in use, reliable cryogenic storage vessels were proved-out and available, and the basic legal, financial and administrative infrastructure of operating a cryonics organization were more or less validated. Procedures for ante- and peri-arrest counseling, standby and transport, cryoprotective perfusion and storage also had been developed and proved out as at least practical to implement in the real world on a sustained basis.

What should have been a blessing arguably proved to be a curse.

Inherent in cryonics is a peculiar vulnerability to what I have variously called the “big fix,” “the one simple solution,” and what Curtis Henderson called the “our friends of the future” syndrome.”  Because cryonics absolutely depends upon people and technology that do not yet exist to carry out repair and reanimation there is the understandably human tendency to shift as much of the burdensome work of doing cryonics onto these “others.”  In this case it is an especially enticing prospect since the limitations of those “others” can conveniently be assumed to approach the infinite, and, even more conveniently, those “others” are not yet born, so they cannot possibly object! Precisely because cryonics professionals had begun to emerge in the US it became possible to add another responsibility shifting behavior to the cryonicists’ repertoire: what Garret Smyth calls the “our friends across the ocean” syndrome.

When Mizar/Alcor UK began to establish capability in Britain there were clear and oft-repeated injunctions from the professionals in the US (chief amongst them me) that you must become autonomous and self-reliant. Yes, we could and would provide you with help of every sort, but ultimately the problem of quality cryonics services in the UK, and by extension Europe, was yours and yours alone. In looking over my letters to various people in the UK group from 1986 onward I see again and again the commands which I have extracted and assembled below, mostly from communications to Max More (nee’ O’Conner) who was President of Mizar, Ltd., the UK cryonics group at the time.

24 MARCH, 1986:
“Your first step, however, should probably be to call a meeting together of all interested parties and do the following:

1) Find out how much they are willing to commit to this endeavour in dollars and cents and in terms of time commitments.

2) Form an organization and elect responsible people. Keep it simple, don’t get grandiose. Initially you might be just an association or club, or you might want to go ahead and do the British equivalent of incorporating
(I’ll provide you with a copy of our Articles of Incorporation and of our Bylaws). If you do incorporate, you will probably find you can do so with minimal expense without the help of a lawyer. Find out if ”self-help” or “how-to” books on incorporation are available. If not, shop around for the cheapest lawyer and get it done. Incorporating or otherwise limiting your liability is probably not a bad idea from the start, since you will, from practically day 1, be handling money and acquiring equipment.

3) Pick someone to work with you, someone who is reliable and will get things done. This person should be Secretary or Secretary/Treasurer. Try to get someone with a proven track history of communication skills—i.e., someone who will WRITE letters and, if they are going to handle money, someone who will keep records—reliably. The Secretary/Treasurer is by far the most powerful person in any cryonics group (sometimes the president has to play all three roles—but be anxious and keep looking around to shift off some of these responsibilities to others ASAPl). You will also need this close someone” to provide moral support, help with planning, and just be there when you need to talk. Pick this person on the basis of personal compatibility as well as to skills.

One other major problem to be on the watch for; I call it the “I’ll take anything ’cause it’s all I got” syndrome. To some extent you’ll have to. Because the pool of people you’ll be working with will be so small, you’ll often find yourself dealing with people who are; incompetent, lazy, liars, exaggerators or all of the above. The average human being does NOTHING unless he has to, but will commit to doing almost anything you ask him to on the spur of the moment (for reasons of ego, pride…). Naturally, he won’t deliver.  It’s your job to be firm with such people. When someone causes real heartache by failing to deliver on a commitment—don’t hesitate to let him and the rest of the group know this. Show that you mean business. When you get someone who truly is worthless, don’t let them lie to you and don’t lie to yourself. One of the hardest myths to overcome is the myth that “there is safety in numbers”. Sometimes we tend to let human zeroes hang around and damage us because the physical presence of another warm body makes us feel more secure. Keep the leadership streamlined to really working people and let “hangers-on” know that they are welcome but they are not full members of the group until they at least “sign up”.

Cryonics is a powerful idea. It is also a good idea. Of all the ideas in the world today, few have the power to save more lives or improve human well-being more than cryonics. It would take me pages to argue why this is so, so I won’t do it here. Perhaps the most powerful argument I can give for you making a commitment to cryonics is that leaving its broader social implications aside, cryonics is almost certainly the only thing that’s likely to save your life. That’s perhaps the best reason of all for “going for it.”  Along the way you’ll have adventures you never dreamed possible and experience personal growth on a scale few people can imagine. If you stick with it, you’ll be a carpenter, engineer, talk show personality, emergency medical specialist and much, much more. In a world of specialists you’ll find cryonics has made you into a renaissance man almost singlehandedly. You will have obeyed Heinlein’s dictum about being good at solving an equation, being a carpenter, speaking in public…in short being a human being in full command of and with full use of your potentials and capabilities. This is a very rare thing indeed.”

11 October, 1986:

Yes, I can arrange training for you, and I can send you a copy of the new TRANSPORT PROTOCOL MANUAL. But, and this point is as important if not more important than any other I will make: The process of achieving the technical capability to *do* cryonics is a long, slow slog. You will need to recruit and to mentor medical and paramedical professionals and this will not happen overnight. If our experience here in the US is any guide, it will take years, perhaps a decade or more to achieve. In order to get such people you will first have to create an environment to attract them and to allow them to learn the procedures and the mind-set that are unique to cryonics, and give them the tools and facilities to practice the melding of their knowledge and skills with those hard won by those of us who have been doing cryonics for on to 20-years now.

Jerry Leaf came into cryonics not only because he was interested and saw the urgent need for his skills, but because serious efforts to create a cryonics capability had been made over a sustained period of time; people were cryopreserved, there were sincere and rational efforts to achieve effective cryoprotective perfusion, and above all, there were places for him to work (the Alcor and Trans Time facilities). These places sat for years with little use, and, truth to tell, even after Jerry became involved and set up Cryovita, Cryovita was a dusty, almost always deserted warehouse full of equipment. It took several years of such seemingly futile operation (with Jerry footing the huge monthly bill for the lease) before a critical mass was achieved when I arrived on the scene and Hugh Hixon became involved full time.  Even with Hugh, Jerry and I working very hard (Jerry and I have full-time jobs) it has taken us  4-years of punishing effort to get to the point where we have what I can honestly call technical competence, if not technical excellence. We have had to create an animal research program (dog TBW, rabbit and cat cryoprotection/ultrastructure) in order to provide the frequent practice and the validation required to master not only conventional clinical perfusion, but to adapt and extend it to cryonics.

It is all too easy to mistake the above for technical mastery when in fact it is really about vision, dogged persistence, and above all LEADERSHIP. You must understand and accept that you will be *alone* in your convictions and yet surrounded by people who will tell you, relentlessly, “you (we) can’t do that, we don’t have enough people, and we must wait for a millionaire to provide the capital because we have no money…” and on and on.  This is pernicious and must not be tolerated. Leadership is not about persuading others to do foolish things for which there is no hope of success. Indeed, if we hadn’t had the success we’ve had here in the US, I would tell you to forget the whole enterprise. However, the fact is that we started with nothing but the meager resources of a couple of working stiffs. We began storage operations here with one guy and only one guy committed to caring for the patients: me. This was only possible for me because I have one day during the week off from my dialysis job and this allows me to take LN2 deliveries.

There was much nay saying and some near panic at the notion that Alcor should store its own patients as opposed to contracting this most central and most critical responsibility out to a company that had allowed one of our patients to warm from up from -196⁰C to -55⁰C due to carelessness. The decision to care for our patients was one of the best decisions we ever made. Patients provide the ground substance of the organization and serve to weld people together enabling them to better weather the inevitable interpersonal differences and even internecine fighting to which all organizations are vulnerable. And so, to my final points; you must understand that while you may be tempted to see yourself as “Alcor” and that the local media will brand you as an extension of Alcor (USA), this is not the case.

We cannot presume to run things for you 3,000 miles away by remote control with money which is not ours, people who do not work with us every day (and may scarcely know us), all while navigating through the dangerous nuances of a different culture and a radically different medico-legal system. In short, as Ayn Rand would say, “we can’t pinch hit living your lives for you.” Sooner, rather than later, you must take on the full range of services; and while there will likely be people in Alcor who will be opposed to this (especially where storage is concerned) you must nevertheless do it. It is YOU to whom your members and patients are entrusting their lives – and you and only you- can discharge that responsibility properly. If YOU are not confident enough to undertake storage, then how on earth do you expect anyone else to have confidence in your ability to lead and endure? Always remember, you have a wonderful advantage which we did not enjoy, namely that should you find storage unsustainable, we exist and we will be there to help you. Of course, and this is no small thing, the reverse is also true. As of this time we are operating more or less illegally here in California since the Department of Health Services (DHS) considers cryonics illegal and has refused to issue disposition permits. This hasn’t been a problem recently because all our patients have been neuro. But, it may well be a problem in the future. Cryonics needs diversification and redundancy in every area and this should be your penultimate mission in the UK.

I reproduce these lengthily quotes from the past because they demonstrate that fundamental lessons learned from experience doing cryonics in the US were not followed. I am not concerned with attaching blame here since that is a sterile and useless exercise.  Indeed, there would be no point to this at all except for two issues, one pressing, and one that could arguably wait a bit. The less urgent issue is to document the historical record: what happened, apart from any analysis, is important to set down accurately because it can serve to inform those who may come after us; saving them from error and allowing faster progress. The more urgent matter is that what happened to cryonics in the UK is part of a situation still in operation to this day, and it is this situation which poses a very real threat to the lives and wellbeing of UK and European cryonicists.

Recently Alan Sinclair has written (sic): “I am always amazed how selective peoples memories are,” when discussing how the Alcor UK facility came to be sold.

I agree that memories can be selective and this why I have endeavored to contact primary sources and obtain first-hand recollections. In some cases I have my own clear recollections backed-up by references in correspondence from the period.

Alan goes on to say (sic): When Alcor UK was build it had a STORAGE BAY long time storage was always a possibility but WHO WAS GOING TO RUN THE STORAGE SIDE not me, I soon realized most people in cryonics in the UK at that time and in fact now are happy to have everything required providing they don’t have to lift a finger to help.”

One sentence later he writes (sic): “The facility closed by unrelated problems, there was little reason after many years of running why the facility which had a fully fitted operating room a separate storage facility designed with the advise of Mike Darwin and a EXACT COPY of the Alcor riverside facility (minas the cryovita section) where Alcor patients were stored at the time so any nonsense of not wanting storage is just that.”

These two statements stand in contradiction to each other and also stand in contradiction to my recollections of our conversations on this subject at the time (backed up by mention in related correspondence sent a few days later). While the facility was indeed built to accommodate storage, I remember my dismay upon arriving at the European Cryonics Conference (October 26-28, 1990) only to discover that Alan did not want to do storage and that he had no intention of doing storage. Alan and I had a comparatively emotional discussion over that issue (at the Thatched Cottage the evening following the tour of the Alcor UK facility) and the reasons he gave at that time bear no relationship to those he has given above. As noted in a subsequent communication to Alcor Directors:

5 November, 1990:

“Alan Sinclair has, he says, decided not to pursue to storage of patients in the UK. He stated that he had configured the facility for storage only in the event that we encounter problems in the US or that other contingencies might necessitate initiating patient care. He seems to have two primary reasons for making this decision. The first reason is that he does not believe storage would be legal in the Eastbourne facility and he cites the lack of clear, authorizing language in the Anatomy Act along with (un-sourced) concerns that being a licensed cemetery is a requirement for storing “dead bodies.” His second concern seems decidedly more selfish and also (as a consequence) more understandable. He feels strongly that we in the US have a better chance for long-term organizational success, or in other words, that he has a better chance of personal survival if he trusts his storage to Alcor in the US rather than to Alcor in the UK.

Needless to say, I find this attitude really troubling, and I think it dangerous to Alcor UK’s stability and prospects for long term success. Because of his enormous financial input, doggedness in discussion (he wins by wearing down as much as by reason) and extraordinary manual and engineering skill, Alan has become more or less the de facto leader of Alcor UK. As such, his confidence, or lack thereof, may prove critical to the survival of the group when the first real crisis occurs somewhere down the line.”

When Alan writes (sic), “I soon realized most people in cryonics in the UK at that time and in fact now are happy to have everything required providing they don’t have to lift a finger to help” I can understand his frustration and even resentment, but a careful analysis of the situation at the time the decision to dispose of the Alcor UK facility was taken tells a different story, as do the events leading up to that decision. In the decade prior to the sale of the building Alan had repeatedly asked for and received greater financial participation in the Alcor UK facility. In fact, at the time the decision to sell was taken Alan was a minority shareholder with approximately 1/4th interest in the property. Far from no one lifting a finger or providing a penny, the members of Alcor UK had taken on the lion’s share of the investment in the property. In particular, Mike Price had become a majority shareholder.

I have spoken with Mike (and with others) who were involved at that time. I have asked Mike specifically for his reasons for deciding to sell the building since he had the power to veto such a sale. The reasons he gives are instructive and very much at odds with the account Alan gives. Mike stated that he began to doubt the personal utility of cryonics sometime in the mid to late 1990s because he came to believe that advancing medical and artificial intelligence technologies, coupled with existing life and health-extension via vitamin supplementation, would allow him to live indefinitely, without needing to be cryopreserved using unperfected methods.  Despite holding this opinion he was not, he has stated, in any way considering disposing of the Eastbourne facility. Certainly, this change of mind was of great importance in taking the decision when it came, but it was neither the initiating event nor the proximate reason.

Mike gives the following reasons as the proximate causes of the decision to cash out his shares and dispose of the building:
1)    Alcor US, under management by Fred and Linda Chamberlain, began a series of draconian changes in requirements for membership in Alcor, principally that all paperwork be executed in English, that all insurance be issued by US companies and that (as a consequence) the member physically be present in the US to purchase the policy and undergo the required history and physical. Further, there were indications that support for carrying out standbys and cryoprotective perfusion might soon be withdrawn. It was clear that what was really happening was that Alcor US was, in effect, cutting Alcor UK loose – walking away from their UK members without the good grace to tell them clearly and unequivocally that that was their intention.
2)    These policy changes by Alcor US lead to what Mike Price describes as “bitter conflict” resulting in “much bad blood within Alcor UK over the issue of what should be done.” Mike has stated that while he, Garret Smyth and some others in Alcor UK advocated “simply doing things on our own and forgetting about the problems in the US,” the group became polarized over the issue of switching arrangements to CI or remaining with Alcor.
3)    At that time Alan had switched his arrangements to CI and publicly stated that “CI does the same or better job for far less money.” The group became divided and, as Mike has noted, any thoughts of pursuing an independent operation and storing patients in the UK became impossible.

A number of others in Alcor UK have remarked that Alan frequently “threatened” to sell the building, starting as early as two years after it was purchased. My own recollections of this are both clear and unpleasant because this tactic resulted in a stream of Alcor UK member calls expressing distress and fear at the prospect of losing their local cryonics capability. I well remember long conversations between Carlos Mondragon (then Alcor President), Jerry Leaf, and myself discussing how to handle this problem. It was, in fact, Mike Price, Alcor US (directly using US funds) , and Alcor US and Mike acting as proxies for other members in Alcor UK, who progressively bought up Alan’s shares in the building.

When Alan says (sic), “Yes I built the unit yes I supplied £350K money but I offered the members 180 £1000 shares that half price to buy the whole facility so we it could be owned and run by a collective but as I recall 3 took up the offer and only 1 was a large share holder who wanted to get out by the time the UK facility closed.(these figures may not be exact but close).” I would agree that Mike Price was certainly the largest shareholder, and the individual who put the most money on the line, other than Alan. However, this discounts the extraordinary effort put forth by Alcor US management at the time, who not only voted to buy shares in the UK facility, but did so in part using patient care fund money. This was done for the reason that all of us at that time felt the UK facility was invaluable and should be retained even at the risk of precious patient care fund capital. In fact the justifying reason for using patient care fund money was that the UK facility served as a potentially vital safe haven to where the patients could be evacuated should storage become impossible for us in the US.

As to what transpired at the end, Mike Price gives the following account in response to questions from me about how things unfolded:

“Alan did not force the sale of the building — it was very definitely a *mutual decision*that both groups agreed with.  What happened was that there was a final meeting, at Alan’s place, between what we can loosely call the “CI group” and the “Alcor group” to see if we could patch our differences up.  It became clear that we couldn’t and both groups split to chew things over.

I left in the Alcor group, obviously, (with Andrew Clifford, Sue, Tim, and possibly a few others).  We stopped off a few miles along the coast road and swiftly decided that that we would have to sell the building.  As I recall it, we sent a text message to Alan to that effect, which crossed over with a message from Alan saying the same thing.  Who *sent* which message first I’m not sure (probably Alan), but the *decision* was very definitely made independently by both groups.  Alan should not be regarded as the instigator of the decision — indeed he asked me to reconsider a few days later, but I felt that the Rubicon had been crossed, too much bad blood had been spilt and I was just sick to death of everything. I wanted out.

A few days later I sent out an email to everyone saying that I didn’t wish to be the largest shareholder any more. As I recall I gave people to a week to let me know of any offers to buy out most of my share.  To which there was a resounding silence from everyone except Andrew Clifford who offered to increase his stake (although not by enough on his own).

Re: UK storage. I distinctly recall telling the combined group (either at that final meeting, or a just prior one) that this was a golden opportunity for us in the UK to go for our own storage and put the US schisms behind us, and don’t recall getting a positive response or public backing from *anyone* in *either* group.  The most “positive” responses were along the lines of “yeah, right, but who are we going to go with, CI or Alcor?” which I found incredibly frustrating.  Perhaps some people did agree with me, but I don’t remember getting any strong public backing at the critical time (which was needed), and I clearly recall my bitter frustration at this.”

As Mike Price commented when I spoke with him by phone on 19 July,2008, “had we (Alcor UK) had patient storage capability the whole debate over CI vs. Alcor and the resulting bad blood would never have happened. We would have just carried on and remained unified as a group of people who wanted cryonics and was providing it for themselves.”

I believe the above is a reasonably concise and accurate account of what transpired and why. If I have made any errors in this narrative I would ask that Alan, and any others with certain knowledge, bring them to my attention.

What I have never understood about the objection of Alan and a number of the other members to cryopatient storage in the UK, on the basis of there being insufficient manpower, is that patient storage is the least labor intensive part of cryonics operations. If a group cannot muster reliable staff to store patients then they have absolutely no hope of mustering sufficient and reliable personnel to perform standby and transport operations. How is a time and labor-sensitive area of operations which must go on indefinitely and be ready round-the-clock be feasible, while patient storage is not?

I know all too well from personal experience that it is very easy to sit about and criticize someone with 20-20 hindsight. This is especially galling when the critic or critics wearing the retro-spectacles have never even bothered to bestir themselves from the chair from whence they make their “sage” observations. While many criticisms of me are possible and justified, I cannot be accused of not having entered the fray, taken my wounds, and shed my blood with the best of them. I would be more than happy to leave this history to the past, but the situation is such that the events of those days, and their underlying causes, are still in play, and are affecting the safety and potential survival of UK and European cryonicists now, not the least of whom is you.

Regarding vitrification in the UK Alan has written (sic): “This is correct and they (sic Alcor) are very close for the US but they can’t for the UK until the transport problem is solved. If anyone comes up with that solution everything is in place to vitrify in the UK. The alterative as Mike (Darwin) rightly states is to store in the UK. but who is going to pay for it?” I would like to note that I know of no realistic plans by Alcor to create vitrification capability in the UK. Vitrification as practiced by Alcor is more complicated and more demanding than conventional cryoprotective perfusion and requires sophisticated temperature control, monitoring, and highly experienced personnel to administer it. Indeed, done properly and per specifications, the current Alcor Transport Protocol requires the participation of very well trained and medically experienced personnel who are available not only with little or no notice, but who can remain deployed for several days, if necessary. Historically, Alcor has been unable to muster such a team for deployment to the UK, let alone create one locally in the UK.

What is more, the notion that you can solve the many problems attendant to shipping vitrified patients at LN2 immersion or vapor temperatures by simply contracting out for the purchase of an item of hardware is not the case. Deployment and operation of a shipping unit, as well as loading of the patient, will require trained, and above all, experienced personnel. It is not the same as putting a kettle on the hob to boil water or perhaps more analogously a leg of lamb in the freezer; it will be a complex operation requiring precision timing and much practice. And of course, the fundamental stumbling block, for onto 5 years now, is the hard fact that large quantities of LN2 in the cargo hold are (or are perceived to be) incompatible with safe aircraft operation. It might be a fair analogy to argue that you would have about as much luck trying to ship a 50 gallon drum of aviation petrol by air as cargo. Yes, the plane is loaded with the same stuff, but not only is it carefully packaged (with many safety precautions) its presence is an inescapable necessity for planes to fly. This is not the case with LN2.

Leadership is believing in the people you work with, attracting others to work with you, and, just as importantly, believing in yourself. Making good decisions and following through on them, often against great odds, is certainly what is required for success in cryonics. Over the past 18 years I have watched (and even participated) in UK cryonics being whipsawed in one direction after another (quite apart from the facility or the issue of CI vs. Alcor). I have seen the discouragement demoralize and ultimately immobilize others in UK cryonics, and I’ve seen the rapid and near continuous reconfiguration of facilities leave people bewildered and confused. This latest series of pronouncements over vitrification and shipping is simply a continuation of what has been an ongoing problem.

In the coming years I may be spending a significant fraction of my time outside the US and in the sphere of European cryonics. I like London a great deal, and if I can manage it, I plan to spend as much time here as the law allows. Thus, my interests are far from unselfish and I am going on the record as saying that I think the approach that Alan, and the comparatively small group of UK cryonicists allied with him, are taking is ill conceived and very likely unworkable. It is certainly nothing I’d chance my life on. While not initiated by Alan or the other British cryonicists, the bitter divisiveness caused by Alcor’s misbehavior during the Chamberlain’s tenure of management has been nothing short of disastrous, and I believe that no one would argue that UK cryonics is better off, let alone better poised to take advantage of the increased credibility of, and interest in cryonics based on decisions taken over the last 10 years. I am anxious to see that this changes.

I’ve long noted that two common threads in most of Alan’s communications are the sentiment that not only has he born the lion’s share of the burdens in UK cryonics, but that everyone else has, in effect, done nothing, contributed nothing, and is lazy, incompetent, or both. Even if this were true (which I don’t believe) nothing is gained by repeating it publicly and often. The truth is important and should be spoken. However, frequent repetitions of remarks that discredit the contributions and efforts of its members by the leader of a group mostly serve to advertise failure in leadership and put off any participation that might be forthcoming. The brutal fact is that all cryonics organizations started out based upon the effort of one or two motivated individuals.  Success or failure then depends upon whether that lone man, or at most two or three men, was able to persuade competent others to join him in the fight. This was as true for CI as it was for Alcor; for many years Bob Ettinger labored largely alone to provide patient care and to develop the CI storage system now in use. In fact, it might reasonably be argued that CI solved this problem initially by hiring Andy Zawacki and most recently by attracting Ben Best. In fact it is instructive that all CI operations, including administration, readiness, equipment fabrication,  perfusion, documentation,  cool-down and long term patient storage, as well as the writing of many articles for Long Life magazine, are done by these two men alone!

From 1990 until 2008 no fewer than a dozen patients have flowed into American cryonics facilities from Europe and the Near East. In several cases the patients were extraordinarily wealthy and influential men who would likely have represented an enormous asset to UK cryonics and who could easily have provided the ongoing capital for competent labor (as CI sought and found in Andy Zawacki). One of these patients was a Russian Oligarch, another was a former member of the Russian Federation Duma, and yet another was a petrochemical mogul. There are currently 6-patients in storage in Russia – most of them held privately, at great expense, and being cared for in two cases that I know of by relatives who are both influential and wealthy. For cultural, and in some cases ideological reasons, the US was not an acceptable destination for some of these patients, but the UK might well have been – sadly, we will never know.

Alan himself has written, “If we had all pulled together rather than pulling apart the UK would have a great facility but I have had a steep learning curve and realize its not going to happen until a multi millionaire comes along and gives members all the want for no effort.” This statement is pernicious, false and totally unsupported by the history of cryonics. The injection of large amounts of money into cryonics has mostly resulted in more harm than good and the fundamental administrative and technological advances which have occurred have decidedly not been as a result of the generosity of millionaires. Rather, they have come as the result of the hard work of a few men and women who wanted to do cryonics and who loved it for it was and is that has generated virtually all of progress to date. These men and women may have started out as customers but they became professionals – and for that there is no substitute. Above all they did not whinge that they were too few and thus incapable of action and progress.

It should be made clear that by no means was Alan Sinclair solely responsible for the demise of the UK facility. Others could have and should have stepped up and made commitments, or at very least made their voices heard loudly and clearly, and, with the exception of Andrew Clifford, this did not occur. As we now know in hindsight at about the time that decision was taken I was desperately casting about in the US for a place to work and to house the ~£250,000 worth of cryonics and research equipment I owned. I would have come to the UK in a heartbeat; staying here my allotted 6-months of each year to teach and train – gratis. I note this as a point of instruction for future decision taking in such critical and hard to reverse situations, not as *the* definitive solution to the problem.  From my perspective the disintegration of Alcor UK not only could have been prevented, but almost certainly would have if the group remained unified, in other words, if they saw themselves as people who had to rely only on themselves for their wellbeing and survival. As a unified group they could then carefully identify and consider many choices, and just as importantly, generate an exhaustive list of people to contact who might provide advice, identify additional choices, or even provide material help. At very least, such a determined, patient and dogged approach would have bought a lot of time for thoughtful and unemotional consideration.

Had any other members of the group independently decided to switch to CI it would have mattered naught. However, when Alan Sinclair made that decision it had impact far beyond his personal situation. He was the leader of the group and his decision not only to switch, but to vigorously advocate that others do the same, was not merely a vote of no-confidence in Alcor US (which was fully justified), but also the death knell for Alcor UK. The crucial point here is that it does not seem reasonable that anyone would have taken this decision if they really saw themselves as they were then, and as they remain to this day:  a group of people who are, in the final analysis, on their own. No one in the US is going to come dashing in to save you (they have their own problems to sort out), and if you rely on that you will confront another 18-years of broken promises and abysmal care. Thus, the most golden rule in cryonics is that nobody, absolutely nobody, is going to save your life for you. If you want it you must do it for yourself or you must join another group and relocate to near their facilities. Once you commit to creating a local group, and working to establish cryonics in your own country, you must believe in and fight for that group at all costs short of your very life.

Over this past year I have been scanning in news clippings from the past 4 decades covering cryonics and this has caused me to reflect on the truly terrible crises Alcor endured in the 1980s; most spectacularly the Dora Kent incident and the fight for the legality of cryonics with the California DHS. I did not acquit myself well during the Dora Kent crisis, but, fortunately, others did. Victory seemed impossible and survival unimaginable, at least to me. My lack of courage, or more honestly, common sense (after all, what exactly was our alternative but to fight on?) cost me dearly. But it also taught me what leadership is all about and it gave me the insight and resolve never to make that mistake again.

As I was pondering this matter late one night here in London, Garret Smyth handed me the following quote from Shakespeare’s Henry V. There was much irony in this act for, unbeknownst to Garret, this play, along with Shakespeare’s Richard III, was quoted often and at length by Curtis Henderson as a metaphor for the struggle of cryonics. He and Gillian Cummings would often riff off of each other reciting pages of dialogue at a go.

I therefore think it good and proper to end with those words prefaced with a few more about the battle Agincourt.  While there has been much debate about just how badly the English were outnumbered that day, it is not disputed that there were at least 3 skilled French soldiers for every English soldier. Conventional military wisdom is that victory is impossible when the odds reach or exceed 3 to 1 (against) on the battlefield. Beyond the numerical superiority of the French there was the wretched situation of the English army. They were malnourished, racked with dysentery, and had just marched 260 miles in two-and-a-half weeks!

We do not know what Henry said to his men on the eve, or on the morning of the battle; those words are lost to history. We may, however, fairly presume that the Bard caught the sense of those words and whether they were spoken by Henry on the rain-soaked fields of Agincourt on the morning of 25 October, 1415 (Saint Crispin’s Day) or not, they *were* spoken by Curtis Henderson (more than once) within the confines of the Cryonics Society of New York and Cryo-Span storage facility at Coram, Long Island – spoken as words of instruction and inspiration to a lad who was a would-be cryonics professional in 1972 and 1973. Take these words as I took them, as instruction and inspiration:

WESTMORELAND. O that we now had here
But one ten thousand of those men in England
That do no work to-day!

KING. What’s he that wishes so?
My cousin Westmoreland? No, my fair cousin;
If we are mark’d to die, we are enow
To do our country loss; and if to live,
The fewer men, the greater share of honour.
God’s will! I pray thee, wish not one man more.
By Jove, I am not covetous for gold,
Nor care I who doth feed upon my cost;
It yearns me not if men my garments wear;
Such outward things dwell not in my desires.
But if it be a sin to covet honour,
I am the most offending soul alive.
No, faith, my coz, wish not a man from England.
God’s peace! I would not lose so great an honour
As one man more methinks would share from me
For the best hope I have. O, do not wish one more!
Rather proclaim it, Westmoreland, through my host,
That he which hath no stomach to this fight,
Let him depart; his passport shall be made,
And crowns for convoy put into his purse;
We would not die in that man’s company
That fears his fellowship to die with us.
This day is call’d the feast of Crispian.
He that outlives this day, and comes safe home,
Will stand a tip-toe when this day is nam’d,
And rouse him at the name of Crispian.
He that shall live this day, and see old age,
Will yearly on the vigil feast his neighbours,
And say ‘To-morrow is Saint Crispian.’
Then will he strip his sleeve and show his scars,
And say ‘These wounds I had on Crispian’s day.’
Old men forget; yet all shall be forgot,
But he’ll remember, with advantages,
What feats he did that day. Then shall our names,
Familiar in his mouth as household words-
Harry the King, Bedford and Exeter,
Warwick and Talbot, Salisbury and Gloucester-
Be in their flowing cups freshly rememb’red.
This story shall the good man teach his son;
And Crispin Crispian shall ne’er go by,
From this day to the ending of the world,
But we in it shall be remembered-
We few, we happy few, we band of brothers;
For he to-day that sheds his blood with me
Shall be my brother; be he ne’er so vile,
This day shall gentle his condition;
And gentlemen in England now-a-bed
Shall think themselves accurs’d they were not here,
And hold their manhoods cheap whiles any speaks
That fought with us upon Saint Crispin’s day.

Henry, and his men, won the Battle of Agincourt that day; they not only routed the French, they crushed them and annihilated a goodly share of the nobility in the process. Henry not only made it to Calais (his initial objective), he went on to become the regent and heir to the French throne under the terms of the Treaty of Troyes in 1420. It also bears noting that Henry’s victory was not simply a miraculous triumph of will and courage, but also of technological savvy.  Henry’s army was comprised of 80% archers equipped with Welsh longbows. The French had a few archers equipped with crossbows. Today, it is difficult for us to understand the power of the longbow. It could easily pierce the armour of the time, pass through a man and pin him to his horse or to the ground. It has been estimated that Henry’s ~6,000 arches discharged an average of 60 to 70 arrows a minute with a fair degree of accuracy. This was, then, the medieval equivalent to deploying a company of machine gunners against the French at Agincourt. As I said earlier, there is no substitute for selecting the right technology. Both leadership and good judgment are required for victory.

In the UK, from 1990 on, there was a terrible reluctance to grasp the nettle and take on the full burden of cryonics by and for British cryonicists. This reluctance was understandable in that accepting the responsibility to care for patients in long term cryogenic storage is a huge obligation, and one which involves considerable day-to-day effort. I know that one very legitimate concern Alan Sinclair had (which was shared by others in UK cryonics at the time) was that there were not enough truly committed cryonicists in Britain to ensure the success of such an open-ended undertaking. I have no doubt that this was true then, no doubt that it is true now, and no doubt that it was true for both Alcor and CI when they (respectively) made the decision to commence storage operations. In fact, I would go so far as to say that this still true for both organizations: can you ever have enough truly committed cryonicists to ensure the success the success of the indefinite care of cryopatients? Since I was the foremost advocate of undertaking storage of patients at Alcor in 1981 (and one of 3 people responsible for the final decision) I can speak with authority about the fear and uncertainty that accompanied that decision.

A common English-language idiom, which is also the title for this essay, is to “grasp the nettle.” This is a particularly appropriate idiom and metaphor in the case of UK cryonics. Urtica dioica, or the stinging nettle as it is more commonly known, is a ubiquitous weed here in the UK. The stings are quite painful and even the gentlest contact will leave a fiery rash of stings. However, if the plant is grasped firmly with the bare hand, crushing the stingers instead of allowing them to penetrate the skin, the plant may be safely handled. Unfortunately, there is a natural hesitancy when grabbing a nettle and it is almost a given that first time practitioners of such bare-fisted tactics close their hand too gently and too slowly, and so get stung.  Cryonics will be reborn in the UK sooner or later. I believe that that time is now at hand. However, regardless if I am wrong or right on that point, I am certain that when the time comes it will be essential that British cryonicists act with resolve and accept full and complete responsibility for their own wellbeing – including for their long-term cryogenic care.

D(+)-Lactose and other sugars in organ preservation and cryonics

A PDF file of this document is available with images and structural visualization of various sugars.

D(+) lactose monohydrate is the principal sugar in mammalian milks. The monohydrate part is easiest to explain; it simply means that the lactose molecule has one water molecule attached to it. This is important because some chemicals can have a lot of water molecules attached to them. For instance, you can have magnesium chloride with two attached water molecules (dihydrate) or six attached water molecules (pentahydrate). This becomes very important when you are weighing out a chemical and you need the chemical to be present in the correct amount. You’ll understand how important this is if you consider that someone proposes to sell you a kilo of some very valuable chemical (say 100 times more valuable than gold per milligram). There is going to be a considerable difference in the amount (by weight and usually by volume) of the actual active chemical you get per milligram or gram (weight) depending upon how hydrated it is (how many water molecules it has attached. The molecular weight (molecular mass) of magnesium chloride is 203.30 and the molecular weight (MW) of water is 18.01. Now, if you have 6 water molecules for each magnesium chloride molecule you have a total mass of water of  (18.01 x 6) = 108.06. That means if you have the pentahydrate salt of magnesium chloride you must add the weight of the 6 water molecules to the MW of magnesium chloride: 203.30 + 108.06 = 311.36. So, if someone is selling you a gram of magnesium chloride pentahydrate at the same price you can buy magnesium chloride anhydrous (no water) you are getting cheated because you are paying the same price for a gram of product that is 1/3rd water!

In biology and chemistry the same principle applies because if you need a certain amount of a chemical for critical reasons, say to maintain normal cell function or inhibit cell swelling in hypothermia, then you must account for any water molecules that may be attached to the chemical. In the case of magnesium chloride pentahydrate versus anhydrous magnesium chloride you are going to have to weigh out about 1/3rd more of the powder of the pentahydrate salt in order to get the same amount of magnesium chloride present in one gram of the anhydrous salt.

Why have pentahydrate, monohydrates, dihydrates and so on of chemicals? The answer is that some chemicals are almost impossible to handle in room air without rapidly absorbing water. Some chemicals will absorb just so much water and no more and thus are very stable under conditions of normal use, so they are supplied in this form. Some chemicals, especially organic chemicals, are virtually impossible to economically produce without one or more attached water molecules. Magnesium chloride is a really good example because it is intensely hygroscopic; it will literally pull water out of the air right before your eyes. So, not only is anhydrous magnesium chloride more expensive than the pentahydrate, it is virtually impossible to handle. If you try to weigh it out it will literally be grabbing water from the ambient air so fast that you can’t tare it on the scale. In seconds you will see tiny droplets of water on the weighing boat or paper where the magnesium chloride has literally pulled so much water out of the air it is fully dissolved in a tiny droplet of water! Calcium chloride is just about as bad, so, you’ll notice that we don’t even bother trying to weigh these chemicals out as dry powders, but rather buy them as pharmaceutical products for injection because they are already dissolved in solution in very precise concentrations. Thus, it is much simpler to draw up the correct volume of these salts dissolved in solution to add the desired amount of these two chemicals to perfusate. It is possible to weigh them, but you have to be quick and it helps if you live the desert where the humidity is very low.

Now we come to the D(+) part which is much harder to explain. In the early part of the 19th Century the French physicist Dominique F.J. Arago noticed that when he passed polarized light through quartz crystals the light could be rotated either to the left or right depending upon the individual crystal. Shortly thereafter the brilliant physicist and mathematician Jean Baptise Biot (the Biot number, a dimensionless number used in unsteady-state (or transient) heat transfer calculations, is named after him) also observed this same effect in liquids and gases of organic substances such as turpentine and some other petroleum products. About 10 years later the English astronomer Sir Joun F.W. Herschel discovered that different crystal forms of quartz rotated the linear polarization in different directions. Simple polarimeters have been used since this time to measure the concentrations of monosaccharide sugars, such as glucose, in solution. In fact, one name for glucose, -dextrose-, is so named because it causes linearly polarized light to rotate to the right or “dexter” side. Similarly, levulose, more commonly known as fructose (fruit sugar) causes the plane of polarization to rotate to the left. Fructose is even more strongly levorotatory than glucose is dextrorotatory. Invert sugar which is formed by adding fructose to a solution of glucose, gets its name from the fact that subsequent structural conversion causes the direction of rotation to “invert” from right to left.

The reason for this behaviour of these seemingly identical substances was not understood until the mid-19th Century when Pasteur was working on the problem of why wine was souring as opposed to fermenting into an alcohol solution. The culprit was yeast that metabolized the fructose in the grape juice to tartaric acid. A solution of tartaric acid derived from living things (the wine lees yeasts) rotated the plane of polarization of light passing through it, whereas chemically synthesized tartaric acid prepared by non-organic means in the laboratory did not have this effect. This was puzzling because both the synthetic and the biologically derived tartaric acid undergo the same chemical reactions and are identical in their elemental (atomic) composition. Pasteur noticed that the crystals came in two asymmetric forms that were mirror images of one another. He meticulously sorted the crystals by hand and then dissolved each of the two forms of crystals in water; solutions of one form rotated polarized light clockwise, while the other form rotated light counter-clockwise. An equal mix of the two had no polarizing effect on light. Pasteur deduced the molecule tartaric acid molecule was asymmetric and could exist in two different forms that resemble one another; as would left- and right-hand gloves, and that the organic form of the compound consisted purely of the one type.

This phenomenon is referred to as isomerism and occurs when two molecules have the same molecular formula (atomic composition) yet have different structures and therefore different chemical and physical properties. There are many different kinds of isomers. The two major divisions of isomers are the geometric and the structural. Structural isomers are isomers that have the same number of atoms but different arrangement of atoms. One structural isomer of glucose is fructose. Geometric isomers are identical in arrangement of covalent bonds but are different in the order that the groups are arranged.

A major category is stereoisomers which are two isomers that have the number of atoms in the same order. A stereoisomer of glucose is galactose. In the Fischer projection all of the atoms are the same except for one rotated group. There are two categories of stereoisomers, enantiomers and diastereomers. Enantiomers are two isomers that are mirror images of each other when looked at in 3D while diastereomers are not. Galactose is just one of many diastereomers of glucose. To find out the possible number of stereoisomer forms a monosaccharide can have, you can use the formula 2x where x is the number of chiral carbons the molecule has. Molecular chirality occurs when a sugar has a carbon with four different groups attached to it. Any carbon with a double bond on it is never chiral nor are the end carbons. Because glucose has four chiral carbons there are 24 different stereoisomers; which means that there are sixteen different stereoisomers for glucose.

Two of the main divisions of glucose’s many forms are l-glucose and d-glucose. These two are enantiomers which are determined by whether the two molecules are symmetrical at the last chiral carbon. When the hydroxyl group is on the last chiral carbon on the right it is considered d-glucose  and when it is on the left it is classified as l-glucose. The “d” means that the glucose rotates polarized light to the right (dextrorotatory) and the “l” stands for  levorotary (rotates polarized light to the left). These refer to how a plane of light rotates as it passes through a solution of it. First light is passed through a polarizing filter, then a polarimeter containing a solution made with the molecule. When a d-solution is in the polarimeter it will cause the light to turn to the right or at positive angle, while an l-solution will cause the light to turn to the left or a negative angle. Both d-glucose and l-glucose exist naturally but d-glucose, also called dextrose, is the most abundant sugar on the planet.

The practical biological and chemical implications of these isomeric structural differences is profound. D-glucose (dextrose) is the principal sugar used by the body to generate energy. By contrast, l-glucose cannot be significantly metabolized and an animal or human would starve to death if this was the only carbohydrate available in its diet and no other sources of energy (fats or proteins) were available. L-glucose looks, tastes and has the same mouth feel as d-glucose and there has been considerable interest in producing it in large quantities as an artificial sweetener.  Unfortunately, the synthetic pathway to produce l-glucose, and more importantly, the separation of the d- and l-glucose isomers after synthesis is currently prohibitively expensive.

What does all this have to with cryonics and organ preservation? Under normal metabolic conditions the cells of the body produce chemical energy in the form of ATP and about 1/3rd of this energy is used to pump ions into and out of the cells. This is necessary because the most common salts (ions) are very small and can easily pass through the cell membranes. Two straightforward examples are very much on-point. Cells need high concentrations of the potassium ion inside them to be able to function properly including carrying out some vital chemical reactions and doing things like contracting in the case of muscles or transmitting signals in the case of nerve cells. Conversely, cells must not have too much sodium in them or they  become swollen (edematous) and while this can ultimately rupture or lyse the cell, long before this happens cell swelling disrupts the meshwork of supports that maintain the cell’s shape and probably serve as scaffolding for various enzymes to be anchored on and to facilitate efficient chemical processing (metabolism). Unfortunately, sodium has a net negative charge and the protein inside cells has a net positive charge. Thus, sodium will flow into cells and carry water with it resulting in cellular edema. This process is prevented by active pumping of sodium out of the cell. Similarly, calcium is extremely toxic to cellular mitochondria in high concentrations and calcium is also used as a critical signalling molecule inside cells. Thus, the calcium concentration outside cells is typically 10,000 times higher than that present inside cells. Again, this difference in concentration is maintained largely by active pumping which requires energy expenditure and on-going metabolism.

So, sodium gets pumped out and potassium gets pumped in and this process is linked and carried out by the same molecular machine; the sodium-potassium pump. Of course, all of this presumes that there is both available energy in the form of ATP and that the cellular pumping machinery can use that energy. There are a number of things that can interrupt ion pumping. There can be a lack of energy due to starvation, hypoxia or ischemia, and there can exist situations where the energy is available but cannot be used. Some chemicals poison enzymes critical to ion pumping; a classic example is tetrodotoxin which comes from blowfish and which poisons sodium pumping. The other condition where adequate energy (ATP) can exist but cannot be used is deep hypothermia. Non-hibernating animals have enzymes that shut down or become inactive when the temperature is reduced well below that of normal body temperature. In humans (and most non-hibernating mammals) the  enzyme responsible for pumping sodium out of cells and potassium into them, sodium-potassium-ATPase, is largely inhibited at 10oC and is virtually shut down at few degrees above 0 oC.

Cell swelling in brain cells occurs with incredible rapidity after interruption of blood flow in ischemia (cardiac arrest). While cell swelling is not the only, or even primary, cause of injury in cerebral ischemia, it is a major player in causing injury in cold ischemia; conditions which obviously obtain in organ preservation and ultra-profound hypothermia in cryonics patients. The way this edema is prevented in organ preservation is to replace almost all of the small cell membrane permeable ions with big molecules that cannot pass through the cell membrane and which are osmotically active; in others words can hold water outside of the cell.  The first solution to do this with any success was Collin’s Solution invented by Geoff Collins. It used comparatively large phosphate salts to keep water outside of the cells and prevent cellular edema. However, phosphates do leak across the cell membrane and they are incompatible with DMSO and also precipitate as crystals when solutions are cooled to low temperatures or frozen.

Thus, the organ preservationists turned to sugars and sugar alcohols as molecules to serve as an osmotic agent and prevent cell swelling. Sugars are comparatively large molecules and some are very large. They do not typically pass through cell membranes rapidly, if at all. Some of the first sugars tried were glucose and sucrose and the sugar-alcohol mannitol. Neither glucose nor sucrose worked well. Glucose leaks across cell membranes fairly rapidly and has facilitated transport in the brain. Sucrose makes quite viscous solutions in the necessary concentrations (~180 mM) and for unknown reasons is toxic to the kidney tubule cells. Mannitol was much more successful in the laboratory but never made it into clinical organ preservation solutions.

In the 1980s, a biochemist named Jim Southard and a transplant surgeon named Folkert Belzer began to systematically study molecules to inhibit cold ischemic swelling, as well as other molecules to help conserve ATP, inhibit free radical damage, and otherwise address the derangements that occur under deep hypothermic conditions. They identified two sugars as particularly effective in inhibiting cold ischemic cellular edema, raffinose and lactobionate. They combined these two sugars along with other ingredients to create the first and still most successful “universal” organ preservation solution, UW-Solution, or as it is commercially marketed, Viaspan.

Unfortunately, ViaSpan does not work for the brain. We tried it extensively in the early 1990s and got serious cerebral edema followed by convulsions and death in dogs that had been perfused with ViaSpan for as little as two hours! By contrast, we could recover dogs perfused with MHP (a mannitol based perfusate) after 5-hours of bloodless perfusion with the solution at  5oC with no neurological or other problems; most of the dogs were placed with cryonics members and lived out the rest of their lives normally.

Recently, 21st Century Medicine has been systematically investigating hypothermic organ preservation and they have made a number of stunning breakthroughs. One thing which was long overdue to be done was to systematically screen various molecules for their cell swelling inhibiting effects. They found that one sugar in particular was highly effective, D(+)-lactose. Only the d-isomer worked well.

Why some sugars work and others do not, or actually cause harm, is a mystery. The molecular weight is certainly a factor, but different sugars with nearly identical molecular weights may perform totally differently. Also, the isomer of the sugar appears critical in some cases, as is the situation with lactose.  21st Century Medicine has patented an organ preservation based on D(+)-lactose and is in Phase II clinical trials for this solution, which they call TranSend. They are currently getting 72-hour simple flush and store on ice preservation of kidneys (rabbit and dog), pancreases and livers (dogs) and are getting similar results in the human clinical trials. They have achieved 48-hour heart preservation using a derivative of this solution which combines periods of trickle-flow cold perfusion with brief intervals of modest warming to ~15 oC.

Mike Darwin on obstacles to progress in cryonics

The blog dw2-0 reports on Mike Darwin’s recent ExtroBritannia talk in London:

“Mike Darwin made the same connection at an utterly engrossing UKTA meeting this weekend…. He spoke for over two hours, and continued in a formal Q&A session for another 30 minutes….

….The most poignant part was the description of the people issues during the history of cryonics:

  • People who had (shall we say) unclear ethical propriety (“con-men, frauds, and incompetents”)
  • People who failed to carry out the procedures they had designed – yet still told the world that they had followed the book (with the result that patients’ bodies suffered grievous damage during the cryopreservation process, or during subsequent storage)
  • People who were technically savvy and emotionally very committed yet who lacked sufficient professional and managerial acumen to run a larger organisation
  • People who lacked skills in raising and handling funding
  • People who lacked sufficient skills in market communications – they appeared as cranks rather than credible advocates.”

More here:

Human obstacles to audacious technical advances

Another account of the event here.

Cryonics: why it has failed, and possible ways to fix it

From: ExtroBritannia

Cryonics: Why it has failed, and possible ways to fix it – with Mike Darwin

The next ExtroBritannia event is scheduled for Saturday August 2, 2008; 2:00pm – 4:00pm.

Location to be announced asap.

Lead Speaker: Mike Darwin, President of Alcor Life Extension 1983-1988, Research Director 1988-1992. Described by Wikipedia as “Second only to Robert Ettinger as one of the most influential figures in the controversial field of cryonics”.

The talk will draw on the speaker’s extensive personal experience with cryonics – the low-temperature preservation of humans and other animals that can no longer be sustained by contemporary medicine, until such time in the future when resuscitation may be possible.

The talk will cover: the audacious ambition and vision of cryonics, practical details of how it works, a whistle-stop history of cryonics, issues with the governance of cryonics organizations, factors influencing public perception of cryonics, and reasons for both fear and hope for the future of cryonics.

Special attention will be given to the decline of cryonics in the UK and the failure of UK cryonics to establish a robust, full-service beachhead in Britain. The talk will also highlight what can be done to re-establish cryonics in the UK as a stable enterprise that will deserve the confidence of both its members and the public as a competent, high quality undertaking offering services which meet the highest ethical, scientific and biomedical standards.

The meeting is sponsored by the UK Transhumanist Association. There is no charge to attend. Join the debate!

Discussion is likely to continue after the event, in a nearby pub, for those who are able to stay.

There’s also the option of joining some of the UKTA regulars for drinks/lunch beforehand, starting c. 12.30, in a pub (to be announced). To find us, look out for a table where there’s a copy of Aubrey de Grey’s book “Ending Aging” displayed.

Venue: To Be Announced – somewhere in Central London

Liquid ventilation in cryonics

After legal pronouncement of death, cryonics patients benefit from rapid stabilization to protect the brain from injury. The most fundamental intervention is induction of hypothermia. Unlike other interventions such as cardiopulmonary support (CPS) and administration of neuroprotective medications, induction of hypothermia is an intrinsic part of cryonics. Unfortunately, surface cooling with ice is not a very effective way to rapidly drop the core temperature of the patient. There are a number of alternative cooling methods such as peritoneal, colonic, and gastric lavage but these cooling methods can be logistically challenging and require specific (surgical) skills. As a consequence, application of these cooling methods in cryonics is rare. To date, rapid cooling in cryonics is achieved during blood washout, which requires surgical access to the circulatory system of the patient.

Because the neuroprotective effects of hypothermia on the brain are so profound it would be very desirable to be able to induce rapid cooling without the need for surgery and extracorporeal perfusion. In the mid-1990s, cryonics researcher Mike Darwin realized that one might be able to reap some of the benefits of cardiopulmonary bypass-induced cooling by using cold cyclic lung lavage with an inert liquid. Because all of the patient’s blood travels through the lungs, the lungs can be utilized as an endogenous heat exchanger to cool the patient. With his colleagues at 21st Century Medicine and Critical Care Research (CCR), a number of prototypes were built to deliver and remove chilled perfluorocarbons. Initial canine experiments using this technology were successful and in 2001 a paper was published that documented that cooling rates of 0.5 degrees C/min could be achieved. A number of different terms for this technology have been used including liquid ventilation, mixed-mode liquid ventilation (MMLV), and cold cyclic lung lavage, depending on which aspect of the technology needs emphasis, breathing or cooling.

A basic version of cold cyclic lung lavage with perfluorocarbons was used on Alcor patient A-1876 in 2002. This case constitutes the first documented case of cold cyclic lung lavage in cryonics. Although the case summary states that “the combination of external cooling in the ice bath and fluorocarbon cooling via the lungs had reduced her core temperature from around 36 degrees Celsius at the time of death to approximately 9 degrees in just two-and-a-half hours,” no specific details on the equipment or procedure are given. The report does indicate that rapid indication of hypothermia by delivering and removing cold perfluorocarbons from the lungs is technically feasible in cryonics patients. In 2007, the cryonics company Suspended Animation and CCR reported on the development and fabrication of advanced automated prototypes to induce liquid ventilation that can achieve cooling rates superior to the prior art. The recent prototypes are scaled for human lung volumes and could be used in a cryonics case if people are appropriately trained. Although the concept of liquid breathing is not new, the application of such technologies to induce rapid hypothermia to protect the brain is another example of how cryonics research can contribute to mainstream (emergency) medicine.

Remote blood washout in cryonics

One argument that is often raised in favor of “field vitrification” (or vehicle based vitrification) is that it will reduce the time of (cold) ischemia and eliminate the harmful effects of remote blood washout and transport of a patient on water ice to a cryonics facility. A related argument is that field vitrification will eliminate stabilization.

In fact, field vitrification will not eliminate the need for stabilization because patients need to be protected from warm ischemic injury after cardiac arrest until a location to carry out cryoprotectant perfusion has been secured and surgical access to the patient’s vessels has been established (a procedure that, in cryonics, takes at least fifteen minutes under the best of circumstances). During that period the patient will still require prompt cardiopulmonary support, induction of hypothermia, and administration of anticoagulants and neuroprotective agents. As a consequence, stabilization times should not differ between field vitrification or remote blood washout. In light of the possibility that field vitrification will likely require more demanding and time-consuming surgery, field vitrification might even necessitate longer stabilization times. The only procedure that could reduce or eliminate stabilization would be hospital-based vitrification.

Field vitrification will reduce the period between cardiac arrest and the start of cryoprotective perfusion. But whether this is a clear advantage or not depends on the question of whether remote blood washout and transport on water ice introduces additional injury to the patient. Recent anecdotal observations of cryoprotective perfusion of patients who have been washed out in the field indicate that the procedure of blood washout itself may be harmful. It is not clear, however, whether this is an intrinsic element of remote blood washout and cold transport or the result of poor perfusion techniques and flawed composition of the organ preservation solutions that are used to replace the blood.

In cryonics, remote blood washout is done for at least three reasons: (1) to eliminate the possibility of blood clotting and hypothermia-induced red cell membrane rigidity, rouleaux formation, and cold agglutination; (2) to remove ischemia-induced inflammatory products and endotoxins from the circulation; and (3) to protect the patient from hypothermia-induced cell injury and edema by substituting the blood with an organ preservation solution.

The organ preservation solution used today is called MHP-2. The original MHP solution is a modification of RPS-2 (an organ preservation solution for hypothermic kidney preservation created by Greg Fahy at the American Red Cross) and stands for Mannitol-Hepes-Perfusate. It is designed as a so called “intracellular” organ transplant solution. In order to reduce passive ion exchange as a result of hypothermia-induced cell membrane pump inhibition, its composition more closely resembles the composition of the solution inside the cell rather than the interstitial fluid or blood plasma. MHP also contains molecules to provide oncotic support, prevent acidosis, and reduce free radical damage. In a series of groundbreaking experiments by Jerry Leaf and Michael Darwin, MHP was successful in resuscitating dogs from up to 5 hours of asanguineous ultraprofound hypothermia. MHP-2 is a modification of MHP that is believed to produce superior results.

A number of arguments have been put forward why remote blood substitution with MHP-2 is not successful in securing viability of the brain during transport, and may even produce adverse effects. The most obvious reason is that MHP has been validated for up to 5 hours of ultraprofound hypothermia, which is not the typical transport time of a cryonics patient. A related problem is that MHP has not been validated in a model that reflects the typical cryonics patient who experiences variable periods of hypoperfusion and warm ischemia prior to and after cardiac arrest. And, unlike the canine asanguineous ultraprofound hypothermia experiments, in cryonics MHP is used as static cold preservation solution instead of being continuously perfused at low flow rates. Although MHP can reportedly recover dogs from up to 3 hours of asanguineous circulatory arrest (clinical death), such a protocol further reduces the time that viability of the brain can be maintained during transport.

Although the MHP patent and the notebooks from the original washout experiments are clear that MHP should be prepared as a hyper-osmolar perfusate (~ 400 mOsm), it has been established that in recent years many batches of MHP have not been mixed with hyper-osmolality as an endpoint, due to a lack of osmometry quality controls. The exact effects of this are unknown but have been hypothesized to explain why recent remote blood washout has produced worse results than in the past, possibly by aggravating, or in the case of a hypo-osmolar perfusate, producing edema. This problem, and the confusion about the exact composition of MHP-2, is briefly discussed in the Suspended Animation case report of Cryonics Institute patient CI-81.

Field vitrification is not the only solution to the limitations of remote blood washout and transport on water ice. Another solution would be to improve the composition of hypothermic organ preservation solutions and perfusion protocols to secure extended periods of cerebral viability during transport. Instead of substituting the patient’s blood with an organ preservation solution, after which the patient is shipped on water ice, the organ preservation solution can be continuously (or intermittently) perfused at low flow rates, similar to machine perfusion in conventional organ preservation, while the patient is being driven in a rescue vehicle to a cryonics facility. This has a number of advantages, including the possibility to sustain aerobic metabolism, improve microcirculation and administer cytoprotective agents.

Although cerebral viability of the brain may be extended by improved organ preservation solutions, there seems to be a fundamental limit to shipping patients in hypothermic circulatory arrest because the remaining energy demands of the brain will need to be satisfied by oxidative phosphorylation (or other energy substrates) at some point. Although it is not known how far these limits can be pushed by static use of organ preservation solutions, it is likely that a protocol of continued hypothermic perfusion of remote cryonics patients will exceed these limits. Like field vitrification, such a protocol will present non-trivial technical and logistical challenges.

This still leaves the question of whether remote blood washout can aggravate injury in ischemic patients unanswered. Since the original canine experiments investigated MHP in healthy animals we do not know if some patients would be better off without a blood washout. Dr. Southard, one of the inventors of Viaspan (also called the University of Wisconsin solution in the scientific literature), discussed similar concerns in a recent interview:

“In clinical organ preservation/transplantation, there are many unexplained incidents of reperfusion injury. This is characterized by delayed graft function in the liver and kidney. We do not see this in our animal models. Thus, there are some differences between how experimental animals and human donor organs respond to organ preservation. The difference may be related to the fact that the UW solution was developed to preserve the “ideal organ.” This is one taken from a relatively young and healthy lab animal donor and transplanted into a healthy recipient. In the clinics, the donors are usually brain-dead (brain trauma), remain in the ICU for periods up to a day or more, are treated for hypotension, and come from an uncontrolled group of donors. Therefore, we are now studying how UW solution preserves organs from the “less-than-ideal” donor. We are simulating the clinical condition by inducing warm ischemia or brain death in experimental animals to determine if UW solution is suitable for these types of organs. If not, we will develop an ideal method to preserve these less-than-ideal donor organs.” (quoted on the old Viaspan website).

Similarly, organ preservation solutions used in cryonics need to be investigated in models that better reflect the typical pre-mortem pathophysiology and post-mortem procedures encountered in cryonics. Developing stabilization technologies and procedures for “less than ideal patients” is an important element in an approach known as “Evidence Based Cryonics.”