Poisoning the Well

Monitoring the CryoCultural Penetration of the Groundwater

By Mike Darwin

There ain’t no justice…

If any press is good press, then cryonics should consider itself blessed indeed; because that perennial bad seed, Robert F. Nelson, is about have a movie made about him – and of course, about cryonics too. Academy Award-winning documentarian Errol Morris (“The Thin Blue Line,” “Standard Operating Procedure“) is set to take on his second narrative feature film (the first was 1991′s “The Dark Wind“) in the form of the screen adaptation of Nelson’s account of Dr. James H. Bedford’s cryopreservation on 12 January, 1967, We Froze the First Man. The book was “co-authored” by Nelson, with writer Sandra Stanley, and published in 1968. The full text of the book as a PDF is available here: http://cryoeuro.eu:8080/pages/viewpageattachments.action?pageId=425990&highlight=WeFrozeTheFirstMan.pdf#Home-attachment-WeFrozeTheFirstMan.pdf

Director Errol Morris with  the cover of Robert Nelson’s We Froze the First Man.

But it gets better. To his credit, Morris isn’t completely credulous, and reportedly the other part of the story covered in the film will be inspired by the National Public Radio’s (NPR) “This American Life” segment entitled, “You’re As Cold As Ice,” in which Nelson was shown to be almost psychopathically without remorse, and completely unwilling to accept any blame for the loss of all of the Cryonics Society of California’s patients at Chatsworth, CA. You can listen to the NPR broadcasts on this topic which are achieved at: http://www.thisamericanlife.org/radio-archives/episode/354/mistakes-were-made/

One can only hope that the screenwriter Zach Helm will be clued in to the truth of “Nelson as scoundrel.” Or, should we hope otherwise, and pray for a movie that makes Nelson the hero Robert Ettinger called him in 1967, 1968, 1980, 1990… According to Variety, We Froze the First Man is supposed to be “a dark comedy that will follow Nelson in the 1960′s as he joined a group of fellow enthusiasts who believed they could cheat death through cryonics.” Sounds just great, doesn’t it?

Helm’s previous writing credits include “Stranger Than Fiction” and “Mr. Magorium’s Wonder Emporium,” with the latter also marking his directorial debut. Morris’ last film was “Standard Operating Procedure,” a 2008 documentary about Abu Ghraib prison, where US soldiers abused and humiliated Iraqui prisoners, and captured it all on video and film. Morris has a reputation as a superb documentarian, and I just can’t tell you all how much I’m looking forward to seeing what he does with Nelson’s twisted epistle.

No word yet on the title, Variety reports it is currently known simply as the “Untitled Cryonics Project” and is being backed by Mandate Pictures and Film Rites.

Why, why, someone please tell me why, I had to be a cryonicist!

Dr. Dre’s “I Need a Doctor

The rain was slapping the windows and it was gray, gray, outside. I couldn’t tell though, because the window had been painted over many, many times. I was in a room with half a dozen or so twenty something’s.  Two were playing pool, a small clutch were laughing and smoking and talking. A few more were engaged in quiet, expletive-laced conversation. One was in a Special K and GB induced stupor, staring blindly in the general direction of the flickering colors of the TV.

I was reading.

The flat screen high def TV was nattering away, and making its pretty colors, and no one was watching it, not even Mr. GB, until –

All of a sudden, the sound took on a cool monotony, and the room fell silent, but for the music. The volume was quickly cranked up by unseen hands, and I looked up from my book, which was, ironically, Larry Johnson’s Frozen. Dr. Dre filled the screen, staring pensively over a cliff’s edge – with the sea rolling away in the distance. Quickly, the scene shifts to rapid fire-fire flashbacks of Dre’s life and career.

Ah, that’s the beauty and the peril of this digital age; there can truly be no permanent forgetting. Clip after clip, image after image flickers on the screen – Dre as Eminem’s protégé, women, parties, events from a life full of rage and excess…

Dre is then in his car, speeding maniacally down what looks to be a section of California’s Pacific Coast Highway. The car flips and flips and becomes completely airborne, and then flips some more, or so it seems. It ends in a catastrophic crash, with the vehicle crushed and mangled in smoking dust.

And it’s at this point that the real action starts. A structure in the distance, which is some kind of hybrid of a 21st Century cathedral and a Brutalist laboratory is shown, and then a quick cut to bustling scientists and physicians working to…? Then Eminem is seen inside the structure, standing next to what looks like the engine from the wrecked automobile. The music takes on a likable rhythm momentarily, to be quickly interrupted by Eminem’s rapping:


I Told the World, one day i would pay it back.

Say it on tape and lay it, record it, so one day That I Could play it back.

But I do not even know if I Believe it when I’m Saying That.

Doubt startin ‘to creep in, everyday it’s just so gray and black.

Hope, I just need a ray of That’

Cause No One Sees My vision,

When I play it for ‘em, They just say it’s wack.

Purpose They Do not Know What dope is.

And I do not know if I was awake or asleep when I wrote this.

All I know is you came to me When I was at my lowest.

You Picked me up, Breathed new life in me. I owe my life to you.

Before the life of me, I do not see Why do not you see like I do.

Purpose is it just me Dawned; you lost was his. See this light in you? It’s dark.

Let me turn on the lights brighten and enlighten me and you.

I do not think you Realize What You Mean To Me, Not the Slightest clue.

‘Cause me and you, we’re like a crew. I was like your sidekick.

You gon ‘want to fight Either When I Get off this fucking mic

Or you gon ‘hug me. But I’m out of options,

There’s Nothing Else I Can Do cause …

[Chorus] I’m about to lose my mind,You’ve been gone for so long,I’m running out of time

I need a doctor, Call me a doctor,I need a doctor, doctor,

To bring me back to life

[Eminem]It Hurts When I See You Struggle.,

You come to me with Ideas.,

You Say That These Are pieces, so I’m puzzled.

’Cause The shit I hear is crazy,

Either you’re getting lazy goal, or you do not believe in you no more.

Seems like your own views, not one you-can form.

Cannot make a decision, you keep yourself Questioning,

Second guessing, and it’s Almost like your begging for my help.

Like, I’m Your Leader.

You’re Supposed to Be My fucking mentor.

I Can endure no more!

I demand you remember who you are!

It Was You, Who Believed in me,

When everyone, WAS telling you, do not sign me.

Everyone At The fucking label, lets tell the Truth.

As Eminem wanders about the facility he finds Dre suspended on cables, a la Robin Cook’s Coma, with his face partially obscured by an oxygen mask. There is a dialysis machine, sans blood tubing and with a darkened screen, momentarily visible in the background amid the clutter of other, Frankenstein-like devices. The chorus’ lyrics (sung by Skyler Gray) keep intoning, “I need a doctor, Call me a doctor, I need a doctor, a doctor, To bring me back to life.”  Skyler Gray, the “Doctor,” floats ethereally in the air as a misty, coalescing and disintegrating image, artfully gesturing with her fingers as she repeats, “I need a doctor, Call me a doctor, I need a doctor, a doctor…”

Eminem confronts Dre suspended in a Perspex cylinder of liquid, with bubbles slowly percolating to the top of the clear fluid… He shouts at him to remember who he was, to return to life…

The men in the room were hypnotized, and legs and feet were oscillating the floor in rhythm with the coarse and angry lyrics. The video closes with Dre not just alive, but rehabilitated into a powerful, muscular mass of manhood. The metaphor is unsubtle: Dre is back after 12 years, and his new album, Detox, is going to be a triumph to go with the new, superman body. The video is an homage of gratitude from Dre to Eminem, for giving him his career, and then breathing new life back into it. The last scene is of Dre looking at his own gravestone embedded in the cemetery lawn. He’s alive and triumphant.

A young black man standing near the pool table opines, in a barely comprehensible urban patois, “Yeah, yeah, yeah that’s how it’s gonna be. They’ll bring you back ta life, and make you anything you wanna be.” To which another lad in the room grinningly retorts, “Not you, muthafucker, they’ll thaw your sorry ass and trash it!” But the patois talking GeNexter is having none of that: “Man you lissen here, I’m gonna get chilled if I need to, and I’m sure as fuck gonna come back, if I can.”

“Well said!” I comented, and then returned to my book.

You can see the music video of “I Need a Doctor” here:


Posted in Cryonics History, Culture & Propaganda, Philosophy | Leave a comment

Last Aid as First Aid for Cryonicists, Part 2

By Mike Darwin

A Bit of Background

This piece, and the previous one in this series, was written over four years ago. The articles which now constitute these first “Last Aid”articles here on Chronosphere were submitted to both the Cryonics Institute and to the Alcor Life Extension Foundation. Both organizations declined to publish them. The reasons given were interesting. One was that the use of “flash” or “jump” drives to store cryonics emergency information and procedures on the persons of members was impractical. I was told that “No one would know what to do with such a thing dangling around a “dead”or dying cryonicist’s neck – and what’s more, a phone number on a metal ID tag or bracelet puts the people caring for the member in touch with the cryonics organization anyway, so why bother with a jump drive”

The second reason given was that cryonics “first aid” was dangerous, and shouldn’t be practiced.  Doing anything to a member/patient could get him autopsied, get the good Samaritan thrown in jail, and in any event, only cryonics organization personnel would, properly, know what to do. A few days ago I was waiting for a prescription to be filled at the local Walgreen’s, and as I walked around waiting, I saw was one of these on the shelf:

Figure 1: Flash drive emergency medical information bracelet which could, in addition to holding a cryonicist’s medical history, can also provide detail  and well illustrated instructions for paramedical, medical and mortuary personnel.

There it was, the commercial implementation of the very idea I’d been trying to sell cryonics organizations on years before. When I got home, I logged on to the Internet and sat slack-jawed at the range of USB flash drive emergency medical information products I saw there. So please, keep this in mind when you come to the section about putting cryo-critical information on flash drives. I have updated that section, but if the tone seems a little gee-whiz, well it’s because it was written about 40 years ago in computing technology time.

Its now a mainstream medical practice for emergency medical and contact information to be put on wearable flash drives, and it’s one that, cryonics aside, may just save your life. You can now store your baseline electrocardiogram, your complete list of medications and supplements, and your complete and search-able medical records and history on your wrist, or around your neck. The latter is becoming increasingly easy for individual patients to obtain as both hospitals and physicians’ offices  go paperless.  And that can be a lifesaver, because many critical treatment decisions are made in a vacuum due to the inability of the patient to communicate the necessary information, his lack of understanding of what is important to communicate, and increasingly, because of the Privacy Rule in the Health Insurance Portability and Accountability Act of 1996 (HIPAA) legislation, which provides severe penalties for “unauthorized” disclosure of personal medical information. This has resulted in hospitals and physicians’ offices refusing to disclose potentially life saving information in an emergency. So please, consider jump drive storage of you medical history and your insurance information and ICE contacts, even if you don’t use it for cryonics.

How Bad is Bad Enough?

To fix a problem you first have to understand that you have one. While all cryonicists understand the idea that time after cardiac arrest without cooling or other stabilization is not good, few can even describe this injury by its proper name; ischemic injury. Fewer still can provide even the barest details about its mechanics and time course, and only a handful of cryonicists would even be able to voice an opinion about at what point in this process they think such damage might become irreversible (short of complete decomposition). Almost none could give reasons as to what constitutes the basis for their opinion. This state of affairs is both unacceptable and dangerous. It is unacceptable because it has been 47 years since cryonics began, and during that time an enormous amount has been learned about the biological basis of personality and memory, and about ischemic injury and ways to reduce, if not eliminate it. Failing to act in the face of such knowledge is inexcusable.

It is dangerous because, absent a solid understanding of the nature and time course of ischemic injury (which at some point becomes more properly described as postmortem decomposition), it is impossible to know what to do, when to do it, or to feel any urgency about taking action. Thus, injury that could have been minimized, or completely avoided, is more likely to occur; and in the worst case, the patient will pass from cardiac arrest into true information-theoretic death. In other words, if you have no idea when bad becomes irreversibly and lethally bad, you have no point of reference, no sense of urgency, and little ability to avoid lethal situations. Under these circumstances cryonics becomes more akin to a ritual, wherein any application of cold to a “corpse” at any point in the decomposition process is deemed not only necessary, but sufficient to assure a chance at recovery.

This situation can only be remedied by detailed information about the damage that results from both warm and cold ischemia, and a clear explication of its likely practical implications for revival, and recovery of personal identity. In one sense it is absolutely the case that, with a change in US law, almost all cryopatients are going to be revived. If human cloning were to be made allowable tomorrow, every cryopatient with an intact genome could be revived, but the question is, as whom? Few of us would be satisfied to see a tabula rosa genetic duplicate be all that is recovered, and many, if not most of us would rightly question if the recovery or creation of such an individual really constituted our personal survival. For most of us, to survive is to remember, and to be the person that decades of unique experiences and unique brain structure have built up and created. In order for us to survive in that form, the fine structure of our brains that encodes those experiences and our unique responses to them, must survive in a sufficiently robust condition to be retrieved and restored to consciousness.

For the first time since the inception of cryonics, it is possible to state with reasonable confidence that essentially complete ultrastructural preservation of the brain is now technologically achievable. This revolutionary change is a result of recent advances in brain cryopreservation, where it has been demonstrated that the ultrastructure of mammalian brains vitrified under controlled conditions (in the absence of ischemic injury) preserves both brain ultrastructure 1-3 and the biochemistry that underlie long-term potentiation (LTP); the mechanism currently believed to be the first (and perhaps the most delicate) step in encoding memories. 5,6

Unfortunately, these results will be meaningless for cryopatients who have suffered loss of identity-critical information before cryopreservation, or who suffer such losses as a result of ischemic injury which interferes with adequate cryoprotection and vitrification or freezing. The frustrating and unbelievable reality is that never in the history of cryonics has the disconnect between what is technically possible, and the reality of what is actually clinically available to human cryopatients, been greater. There can be no doubt that a huge part of the reason for this, is a lack of understanding of how destructive ischemic injury is, and how routinely and often unnecessarily it is happening to cryopatients.  In fact, long ischemic periods, and other substandard care are now the rule for cryopatients, and it is the exceptional patient who receives a level of care even approaching that which is now technically possible.

Cryonics 101: Understanding Ischemia

Take a good, long, hard look at Figure 2 below. It is a snapshot of the ultrastructural changes that go on after cardiac arrest over a 24-hour period in the absence of profound cooling (i.e., to 2 to 4 degrees C). Even the untutored eye can see the deterioration of brain cell structure as ischemic time increases.

Figure 2: In 1984, Jerry Leaf and I undertook a study to try and determine the time course of brain, and other vital organ ultrastructural changes, as a function of ischemic time and temperature. Dogs were anesthetized, placed into cardiac arrest, and then allowed to cool passively to room temperature (RT) where they were held for varying periods of time, up to 24 hours postmortem. Representative results are shown in the six micrographs above. It is interesting to note that by 24 hours of RT ischemia, red blood cells are very rarely seen with either light or electron microscopy, presumable because they have undergone hemolysis. Red cells are rugged compared to brain cells. If they are disappearing what is the fate of the neurons and glial cells?

After 12-hours of warm (room temperature) ischemia in the dog, there is virtually a complete loss of cell (plasma) membrane structure and dramatic degradation of the ground substance; the molecular weave that makes up the cytoplasm of the cell. By 24-hours there are no neuronal or other plasma membranes present and no clearly identifiable synapses. Another way of stating this is to say that sometime between 2 and 12 hours of warm ischemia it is very likely that true (information theoretic) death has occurred. It is also important to understand that these micrographs were made without the additional insults of reperfusion, cryoprotection and freezing or vitrification – or worse still, freezing in the absence of cryoprotection or vitrification because ischemia has rendered the patient impossible to perfuse.

Since the time we did our work on ultrastructural changes in ischemia, the topic has become a subject of interest in mainstream biomedicine. The grim results in our study have been both tempered and confirmed by the work others. In humans who have suffered sudden cardiac death the rate of autolysis appears to be close to that which was observed in our dog work. However, several studies in rats show considerably more conservation of ultrastructure, even at 24 hours postmortem at room temperature.7-10 However, regardless of the rate of autolysis, effective perfusion becomes impossible within a few hours of the onset of cardiac arrest, at best.

While some (capital N Nanotechnology) apologists will no doubt argue that the ultrastructural changes revealed by TEM are really a failure of our current imaging techniques (which rely on chemical fixation and heavy metal staining of tissues to be examined using TEM), few would argue that such changes are not a very bad sign and that they do not constitute an eminently reasonable standard to use in objectifying and broadly quantifying injury from ischemia. Perhaps the best response to those who would minimize the gravity of these changes is simply to ask them, “Which group do you want to be in, one of the experimental groups, or the control?”  Clearly, any rational person with a choice would choose to be as close to the control (no ischemia) group as possible.

The great irony here, is that this is the one technical area in cryonics where we do have an opportunity to choose how much damage we will likely experience, based on our degree of motivation and preparedness. Aside from supporting basic research, there is little we can do to alter the limitations of even the best of today’s vitrification techniques. Research itself is an uncertain business, whose progress is often independent of time and money, and often comes only as a result of overall technological progress. Avoiding ischemic injury is different, we know many ways to do this and for a significant number of cryopatients it is both technically and economically possible, with modest preparation.

Abandon All Hope?

This does not mean that it is irrational or unreasonable to proceed with cryopreservation even if brain ultrastructure looks as bad as it does at 24 hours postmortem in Figure 2, above, if there is absolutely no other alternative. It is possible that a lot of the apparently missing structure might have been washed away during the fixation and preparation process for examination. However, no prudent person would assert that because things might be better than they seem in such a bleak situation, it is acceptable to let such damage occur, when it can be avoided.

We have the same obligation in cryonics that is incumbent upon the rest of medicine, and that is to first do no harm (primum non nocerum). This injunction does not mean that a surgeon cannot wound a patient or that an oncologist cannot administer cytotoxic drugs. What it does mean is that these interventions can only be used when there is a reasonable expectation that they will do more good than harm and further, that we are proscribed from acting in ways that we know, or can reasonably be expected to know, cause damage. There is certainly no good to be gained from allowing the kind of damage to proceed that is seen in the micrographs above and we have the knowledge, the technology, and the resources to avoid it. To fail to use them to prevent this kind of injury is utterly inexcusable.

Knowledge Isn’t Power Unless You Use It

Aside from the lack of vision to do it, a major obstacle to making cryonics first aid a reality has historically been the limitations imposed by the cumbersome technology required to access and transport information. It has long been possible to prepare an encyclopedia of instructions on how to handle cryonics emergencies, but it has not been practical to have that information instantly accessible around the clock, almost anywhere in the world, 365-days-a-year. Nor was it possible, let alone practical, for cryonicists to carry several bound volumes of emergency instructions and detailed procedures with them everywhere they went. And, even if this were practical, say by using microfiche, it would be almost impossible to access the information effectively. This is no longer the case.

The Future Was Yesterday

The average cryonicist is over 30-years-old, and that means that he or she should realize that the developments in computing technology have been fantastically better, and occurred fantastically sooner, than most of us dreamed possible. We can now go almost anywhere in the world and still be connected to vast reservoirs of detailed information that are available to us in amazingly user-friendly ways. If we want to know how to fix a leaky faucet, or how to administer first aid for a wide range of injuries, we can go to Google and type in the words “leaky faucet” or “first aid” and voila, there are a wide range of websites providing detailed instructions and even step-by-step online videos on how to fix faucets or administer first aid for everything from a serious burn to a broken leg. If we need a good recipe for pound cake, want the concept of specific heat explained clearly, or need the value of pi to 20 decimal places, it is all available to us literally at our fingertips and in seconds. That is surely pure science fiction wonder made real to anyone over thirty.

Pictured in Figure 3 is a generic 2 gigabyte USB flash drive which retails for $10.00 US. It can easily be worn as an addition to the standard cryonics emergency stainless steel neck tag. But it suffers from the deficiency that it is not waterproof and it has not been engineered to withstand impacts or harsh conditions

Figure 3: Typical flash drive.

1   USB connector

2  USB mass storage controller device

3   Test points

4    Flash memory chip

5     Crystal oscillator

6     LED

7    Write-protect switch (Optional)

8     Space for second flash memory chip

Figure 3: USB Flash drive memory storage device. Storage capacities are now (2011) as large as 256 GB with steady improvements in size and price per capacity expected. Some flash drives allow 1 million write or erase cycles and have a 10-year data retention cycle.

Figure 4: The Centon 16 gb flash drive is housed in a shock resistant silicone rubber case and is waterproof when closed with the sealing silicone rubber cap.

In the last few years, rugged, military specification flash drives have become available that offer varying degrees of resistance to environmental stress. At the “low”end is the Centon 16 gb DataStick Sport (Figure 4) which has a durable silicon casing with a leak-proof cap design making the drive waterproof and shock resistant which retails for $26.00.At the high end, is the the LaCie XtremKey, with a 64GB capacity and an “impenetrable” shell made of 2mm thick Zamac, a metal alloy composed of zinc, aluminum, magnesium and copper that has extreme crush resistance. The drive seals with a screw cap closure and a rubber O-ring, which makes it water tight to 100 meters. In addition, it’s resistant to 5-meter drops, and is rated to perform in temperatures from +200°C / -50°C (Figure 5).

Figure 5: LaCie XtremKey, with a 64GB capacity with an “impenetrable” shell made of 2mm thick Zamac  metal alloy and a working temperature range of +200°C / -50°C.

Thus, it has been at least 9-years since anyone in cryonics had to be in the position of trying to explain to a mortician, a patient’s family member, or to a willing volunteer what do in an emergency without being able to walk that person through the necessary procedures visually and verbally every step of the way. What’s more, in many instances those instructions could be available for repeated viewing when and where needed, including as the procedures are being carried out. Even something as simple as packing a patient in ice for air transport is in reality not so simple, and it is easy for the attending mortician or volunteers to make a mistake, such as using too little ice, or conversely, heaping ice on the chest and abdomen which puts the patient’s blood under hydrostatic pressure causing it to become a thick sludge, as much of the water filters out of it, and into the tissues.

Figure 6: Neck tag style stainless steel emergency medical information USB jump. drive

There are also now a wide range of emergency medical information flash drives – devices with software designed to capture medical information, organize it, and make it accessible to emergency medical service providers (Figures 6 & 7).

So, why aren’t we using these technologies in cryonics? Why are there no user-friendly, step-by-step emergency cryonics instructions online, or on a jump drive hanging around your neck? What do the 9 paid, full time employees of cryonics organizations (http://www.alcor.org/AboutAlcor/meetalcorstaff.html) do all day, every day, year in and year out? It seems that the future was yesterday, and we cryonicists let pass us by.

Failure to appreciate and embrace this technology has been costly – probably more costly than most cryonicists appreciate. It has prevented cryonicists remote from immediate or very rapid response in the event of an emergency from preparing to help themselves and their families in the most basic ways, such as effectively cooling a patient until help arrives, being able to provide a local paramedic, registry RN, or other person with intravenous access skills with clear, visual, step-by-step instructions on how to give medications that can vastly reduce ischemic injury and maintain the patency of the circulatory system for cryoprotective perfusion – medications and the simple, inexpensive supplies to administer them that all cryonicists at high risk of unanticipated arrest should have on-hand and at-the-ready. In many areas of the world (including the US) paramedical personnel can be found locally on short notice who are capable of administering stabilizing intravenous medications if they have the medications, the administration supplies, and above all the visual, verbal and written instructions available via computer to show them how to do use them. These resources are not being used in large measure because the instructional tools and necessary supplies are not available in emergencies. Indeed, the deeper problem seems to be that cryonics organizations fail to understand that most emergencies are readily foreseeable.

Figure 7: Emergency medical information USB jump drive with accompanying engrave-able neck tag.

How many cryonics organizations have members over age 70, in poor health, at high risk of sudden cardiac arrest (i.e., anyone who has coronary artery disease regardless of whether it has been “successfully” treated) or with a known terminal condition, and yet have provided these members with no resources to deal with an emergency secondary to unexpected death? The answer is: all of them. The implications of this are clear: if you want last aid, you’re going to have to do it yourself.

Below is a short list of instructional presentations that need to be both on-line and on a jump-drive around neck of members who want to exert the effort to be prepared:

Instructional Materials Needed
Title Description
Determining, Pronouncing and Documenting Clinical Death The mechanics of reliably determining and documenting cardiopulmonary arrest (clinical death) for the layman. Guide to use of standard clinical signs: auscultation (stethoscope), pupilllary examination, pulses, BP, fogging of mirror. Guide to objective and evident tests: CapnoMask, CardioSond, mirror test. Documentation of clinical death by the layman: paper records, videography, Nauhtopsy Cam.
Effective Expedient Emergency Cooling How to facilitate effective cooling in a wide range of emergency situations using materials likely to be at hand. This would cover everything from using modified picnic chests to using cold tap water or snow in the winter.
Effective Emergency Cooling Using Specialized Equipment How to use the CephaCool head ice positioner and convective cooler, how to monitor patient core head cooling, how to safely and effectively use non-ice alternatives such as Kwik Kold when ice may not be immediately available.
Emergency Instructions for Cooperating Hospital and Paramedical Personnel Detailed instructions on establishing intravenous or intraosseous venous access for administering stabilizing Transport medications
Preparing and Shipping the Cryoatient on Water Ice How to safely pack the patient in ice and prepare the container for air shipment to the cryonics facility.
Preparing the Cryoatient for Dry Ice Shipment Instructions for how to cool and prepare patients who must be straight frozen for dry ice shipment.
Management of the Autopsied Cryopatient Procedures for handling the patient’s brain and body in the event of an autopsy under a wide range of circumstances; including the procedure for how to straight freeze the brain and protectively package it immediately after the postmortem if it is necessary to do so.

This series of articles is the first step towards solving this problem. If there is genuine interest, the time and talent are available to generate comprehensive, step-by-step photographically and diagrammatically illustrated basic emergency instructions for cryonics first aid, as well as to create data packages for wearable flash drives, so that members’ detailed medical information will also available.  If you would like to see this happen, feel free to contact me at m2darwin@aol.com.

Just how often these kinds of instructions are needed now (and will likely be needed in the future) will be discussed in in upcoming installments, as well information on implementing the first critical element in last aid: the basic theory and practice of cooling the brain effectively, in the absence of Standby and Transport personnel.

End of Part 2


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

2) Wowk B, Fahy GM. Toward large organ vitrification: extremely low critical cooling and warming rates of M22 vitrification solution. Cryobiology 2005; 51:362.

3) Lemler J, Harris, SB, Platt, C, Huffman, T.: The arrest of biological time as a bridge to engineered negligible senescence. Ann NY Acad Sci 2004, 1019:559-563.

4) Hawkins R, Kandel, ER, Bailey, CH.: Molecular Mechanisms of Memory Storage in Aplysia. Biological Bulletin 2006, 210:174-191.

5) LeDoux J: Synaptic Self: How Our Brains Become Who We Are. New York: Penguin Books; 2002.

6) Badonic T, Frumkina LJ, Jakovleva NI, Hornáková A. Ultrastructural changes of neurons in dependence on the death cause in human brain. Funct Dev Morphol. 1992;2(4):231-4. PubMed PMID: 1303105.

7) Hukkanen V, Röyttä M. Autolytic changes of human white matter: an electron microscopic and electrophoretic study. Exp Mol Pathol. 1987 Feb;46(1):31-9. PubMed PMID: 3803537.

8) Schulz U, Hunziker O, Frey H, Schweizer A. Postmortem changes in stereological parameters of cerebral neurons. Pathol Res Pract. 1980;166(2-3):260-70. PubMed PMID: 7393760.

9) Sheleg SV, Lobello JR, Hixon H, Coons SW, Lowry D, Nedzved MK. Stability and autolysis of cortical neurons in post-mortem adult rat brains. Int J Clin Exp Pathol. 2008 Jan 1;1(3):291-9. PubMed PMID: 18784829; PubMed Central PMCID: PMC2480568.

10)Toupalík P, Bouska I, Jezková J. Effect of autolysis on histochemical examinations of the central nervous system. Soud Lek. 2001 Apr;46(2):18-20. Czech. PubMed PMID: 11455721.



Posted in Cryonics Technology (General), Ischemia-Reperfusion Injury, Medicine | Leave a comment

Maxim, Pumps, and Flow Measurement

By Mike Darwin

This post is in response to a comment made by  Abelard Lindsey  on 02-27-2011. Since my response necessitates the use of illustrations, I am making it here, rather than in the comments section.

Abelard Lindsey

If Melody Maxim thinks the existing organizations are so screwed up, she is free to get up off her ass and start a new organization that will do things the way she thinks they should. It’s easyto sit on the sidelines and to criticize the efforts of others. It is more difficult and takes more character and work ethic to get up off of one’s ass and to actually do some effort to make things better.

The ball is in Melody Maxim’s court. Its time for her to put up or shut up.


You know, the ironic thing is, when Maxim first arrived on the scene, I was really pleased, and I looked forward to being able to work with her in some capacity. I had dealt with a number of perfusionists before, and in fact employed two perfusionists when I operated BioPreservation, a cryonics service provider company in the 1990s. My communication with Maxim was necessarily constrained when she was first hired by Suspended Animation, Inc., because I’d learned from previous experience that it is essential to let people gain their own unbiased experience of an enterprise, and especially of a new employment situation, before any negative input is given. Not only is criticizing someone’s employer under such circumstances considered sleazy behavior, it also just doesn’t work. You are perceived as having an axe to grind, being jealous, and so on.

Additionally, my first introduction to her had come in the form of an unexpected phone call from Charles Platt, who put Maxim on the phone to “meet” me. It was a brief (and from my end) awkward conversation. It would have been out of place for me to have then contacted her to criticize SA. I figured she’d come to her own sorry conclusions in due time, and if she was competent, it would be in a short period of time. Subsequently, Charles provided her with a copy of an extensive critique of SA that I had done as a favor (unpaid) to Bill Falloon. I was also asked for specific technical commentary on the in-field extracorporeal circuit for blood washout that SA was trying to develop. There, I apparently made the mistake of disagreeing with Maxim on just one point: the desirability of roller pumps (tubing pumps) over centrifugal pumps for use in such systems. This apparently angered her, and it was all downhill from there. Subsequent interactions with her (at a distance) when she was consulting for CI apparently enraged her.

Her response to my comments about centrifugal pumps in the setting of both asanguineous blood washout/recirculation and cryoprotective perfusion should have been a red flag at the time. At first glance, centrifugal pumps soundly beat roller pumps and other “positive displacement” pumps for extracorporeal support. They are lighter, provide more flow for less power (and weight), do less damage to blood cells, and, most importantly, they cannot pump “bulk” or macro-air into the patient’s circulatory system. If you empty the venous reservoir feeding a centrifugal pump, it loses prime and stops pumping. The impeller continues to spin, but there is no longer any flow. They are thus “inherently safe” in terms of pumping macro-air.

Figure 1: Centrifugal pump at left, and positive displacement roller pump, at right. Centrifugal pumps require a flow measurement device, and in medical applications this is typically an electromagnetic or ultrasonic flow meter, the transducer for which snaps around the tubing, or a special cuvette, as seen at left, above.

So, what’s not to like? When scientific-cryonics got started in the early 1970s, the standard pumps being used in extracorporeal medicine at that time were all positive displacement pumps. Mostly they were roller pumps, but some finger pumps were still in use. A typical roller pump is shown at right, above. A roller pump has two rollers that compress or “milk” the fluid in a section of tubing (the pump “shoe” or “raceway”) by either completely occluding or almost occluding the tubing (Figure 1). They will thus pump almost anything inside the tubing, including air. They also have another feature that can be deadly dangerous in extracorporeal medicine, and that is that if you occlude the outflow of the pump it will keep pumping and increasing pressure until, a) the motor is not powerful enough to continue pumping against the back-pressure, or b) the tubing and/or components in the circuit between the pump and the occlusion explode or come apart (disconnect, or “blow-off”).  One other disadvantage is the action of the rollers on the tubing raceway cause it to spall, or to shed microscopic bits of plastic debris into the blood, and thus into the patient (if not intercepted by the arterial filter). These pumps, despite their seemingly overwhelming disadvantages, were the standard in cardiopulmonary bypass (CPB) until very recently.  And they are still widely used – and they still predominate in the Third World.

Figure 2: Comparison of flow/pressure curves of centrifugal and positive displacement pumps.

While centrifugal pumps have great safety and efficiency advantages, they have some nettlesome downsides. Chief amongst these was that a shaft to drive the impeller had to penetrate the pump housing (left in Figure 1, above) and that meant you needed a seal. This caused all sorts of problems when handling a sterile fluid like blood, and a fluid which could tolerate no contamination. Seals are a source of friction, and thus of particulates. Centrifugal pumps are also almost impossible to adequately clean, and tubing in a roller pump was disposable. Two other problems were that centrifugal pumps are notorious for causing cavitation in the fluid they are pumping. Because they can create regions of very strong negative pressure, they can cause gas bubbles to form – bubbles that subsequently embolize the patient’s circulatory system. The impeller from centrifugal pumps can also generate  enormous shear and turbulence in the liquid, and these cause hemolysis and damage to platelets and white blood cells.

It took decades to design centrifugal pumps that could handle blood “atraumatically,” and when this was finally accomplished, centrifugals performed better than roller pumps under laboratory conditions (there is very little difference clinically in terms of neurological outcome). Since there is no compression of friable tubing in centrifugal pumps, there is also no spallation of plastic particles into the blood. Finally, centrifugal pumps, unlike roller pumps, do not have any rigorous correlation between the rpm of the drive motor and the flow output of the pump. Instead, flow output is a complex function of rpm, torque and back pressure – and so is the developed pressure in the system.  You can see this in Figure 2, above. What this means in practice is that you must have a flow meter to actually measure the flow the pump is producing at any given time. This wasi pretty easily accomplished in industrial applications n the 1970s (and before) by using paddle-wheel, falling ball, or other kinds of in-line flow metering devices. But these solutions don’t work well, or in most cases at all, for blood.

By contrast, every turn of a roller pump will deliver a fairly predictable and uniform bolus of flow. To know your flow, all you have to do is to count the number of rpms, and multiply that number by the volume of fluid displaced with revolution of the rollers. In the early days of CPB, you had to do this by using a “look up table” to convert rmps to flow, based on the diameter of the tuning you were using in the pump head. It was simple, easy and foolproof, but could be dangerously distracting. In the late 1970s, little calculating devices with LED displays did that work for you, and look-up tables taped to the front of the pump console disappeared.

Figure 3: A magnetically-driven, seal-less, injection molded, disposable polycarbonate centrifugal blood pump head.

By the 1980s, huge advances in manufacturing technology made the magnetically-driven, seal-less, injection molded, disposable polycarbonate centrifugal pump head, similar to that shown in Figure 3, not only possible, but economical. Now, the impeller could be driven via magnetic coupling, and no shaft or seals were necessary. Cleaning wasn’t an issue because the whole thing could be thrown away after it was used. And the cost had come down to about $200 per pump head.  Technological advances in “non-wetted” flow measurement made electromagnetic flow meters not only practical, but affordable. So, the flow measurement problem was pretty much solved, as well.  Later, the advent of ultrasonic Doppler flow measurement technology, made flow measurement even more cost effective and accurate.

Why not use these pumps for cryopatients?!!? Unfortunately, it is a characteristic of both electromagnetic and ultrasonic flow measurement devices that the physical properties of the liquid whose flow is being measured matters.  Electromagnetic flow meters only work if a solution has ions or some other magnetic field distorting property – such as being slurry of metal dust, or containing a ferromagnetic molecule…  The washout and cryoprotective perfusion solutions used in cryonics have low concentrations of ions – most of the salts have been replaced with sugars or mannitol (a sugar-alcohol). What’s worse, the concentration of ions will vary wildly and dynamically as perfusion proceeds, because the salts (ions) in the patients’ tissues are being washed out.  Indeed, this is why the more proper name for perfusion to do “blood washout” is called “Total Body Washout (TBW),” because it is not just the blood that is being washed out, but also, to a significant extent, the very chemical composition of the patient’s extracellular space.

Ultrasonic flow meters are intolerant of the huge changes in the micro-particle concentration and the viscosity of the perfusate that occur during TBW and cryoprotective perfusate.  These flow meters are calibrated and optimized in design around blood – and both extracorporeal ultrasonic and electromagnetic flow meters caution the user that they cannot be used with blood containing less than 10 or 20% red blood cells (red cells are, of course, loaded with iron containing hemoglobin, and they scatter ultrasound).  Thus, measuring flow under conditions of TBW and cryoprotective perfusion has proved an intractable problem for over 35 years.

Figure 4: The Manrise model 101 Flow Inducer developed by Fred Chamberlain, the first cryonics perfusion machine, used a Cole-Parmer., Inc., Micro Pump centrifugal pump with a magnetically driven stainless steel and ceramic pump head as the “flow inducer.” A Dwyer Instruments, Co., falling ball flow meter, an in-line analog thermometer, and a sphygmomanometer (connected to a bubble trap) was used as the pressure gauge.

Ironically, given Maxim’s vitriol over cryonicists being “ignorant of centrifugal pump technology,” the first “perfusion machines” developed for cryonics used centrifugal pumps. And that meant they had to have a flow meter.  After much (costly) testing, we settled on a falling ball flow meter, because it performed relatively well across the range of viscosities of perfusates we were using. But please note, this machine was build only for open-circuit perfusion, and blood, even in very small concentrations, renders a solution opaque. If you can’t see the ball, you can’t read the flow… Also, we still had to make look-up tables for each concentration of cryoprotective perfusate to be perfused because falling ball flow meters are sensitive to liquid viscosity.

Figure 5: Extracorporeal Life Safety System (ELS) Bubble Detector and Tubing Clamps for Roller Pumps. http://www.rockymtresearch.com/els.htm

The ELS is an air in line detection safety system indicated for use on roller pump bypass circuits. If air in line is detected both automatic tubing clamps and auditory / visual alarms are activated. The device includes a third clamp for the bridge loop incorporated into roller pump circuits. The Bridge Clamp opens if the line clamps are activated to prevent excessive pressure in the circuit.

Product features include:

  1. Bubble detection: designed so that bubble detection sensitivity can be set down to 10 uL.
  2. Bridge Clamp: The bridge clamp will open the instant air is detected and the patient clamps close. This creates an open circuit to prevent pressure build-up.
  3. Automatic bridge-line “flash”: The bridge clamp can be set to periodically open and flush the bridge line. Duration and interval controls are located on the front panel of the device. Patient clamps remain open during bridge flash cycle.
  4. Manual override on all clamps (all three clamps cannot be closed simultaneously).
  5. Dry-coupled transducer.
  6. Internal battery back-up with automatic recharge.
  7. Compatible with any system.
  8. Simple controls and user interface.

The ELS device has FDA clearance and has been certified by CSA to the IEC 601-1 and UL 2601-1 standards for electrical safety.


Figure 6: LevelSens, a level sensor and detector, notifies operators of low fluid levels in either flexible or rigid reservoirs. Having both medical and industrial applications, the level sensor will alarm audibly and visually when the fluid reservoir level drops below the user-placed sensor and will cease alarming when the fluid level returns. The device does not need to be reset and there is no pump interaction. http://www.rockymtresearch.com/levelsens.htm

  • For Any Flexible or Rigid Fluid Reservoir.
  • Functions on Both Blood and Priming Fluids.
  • Reliable and Simple to Use.
  • No Conflict with Other Devices.
  • Increases Safety. Limits Liability.
  • Powered by a 9 volt Battery.
  • Self Stick, Disposable Sensors.
  • CE Marked


There are two control modules: one designed for use on rigid fluid reservoirs, one designed for flexible fluid reservoirs.

The LevelSens has FDA clearance and has been certified by CSA to IEC 601-1 and UL 2601-1 standards for electrical safety. An independent evaluation has been done by Rocky Mountain Perfusionists of Denver, Colorado. (see abstract)


  • LevelSens – Rigid (Model #201070 for use on rigid reservoirs)
  • LevelSens – Flexible (Model #201110 for use on flexible reservoirs)
  • Disposable sensors – Package of 25 (Product #201073)
    For use with either LevelSens Rigid or Flexible systems. Each package contains 25 individual disposable sensors for use with either the rigid or flexible LevelSens Safety System.

In the intervening decades since this problem was first encountered I, and others, have repeatedly looked at the issue of how to reliably measure flow in perfusates that are dynamically varying in red cell content, ion content, cryoprotective agent content (and thus viscosity) and in temperature (which affects viscosity and  often the performance of the flow meter transducer, as well). I think I have found the solution to the problem (last year, in fact), but for now, I’m keeping it to myself. And when I say found it, I mean just that – I didn’t invent it – it’s yet another artifact of technological advance inflow measurement.

One other problem with medical centrifugal pumps is that they cannot handle the very high viscosity, low flow, terminal phase of cryoprotective perfusion. The pump motor controller is not built to operate under such conditions, and the magnetically coupled impeller will, if the viscosity of the perfusate is too great, simply uncouple from the drive shaft magnet and stop turning.

Because of these issues, and especially because of the flow measurement issue, I recommended that centrifugal pumps not be used for cryonics applications at that time. Yet another reason for my doing this, and feeling comfortable with the safety issues, is that there are now rock-solid, reliable extracorporeal (FDA approved) monitoring systems for both air, overpressure, and reservoir fluid level, which will shut down the roller pump and clamp the blood conducting lines within ~ 300 msec of detecting a problem (Figure 5). The latest generation of low reservoir sensors will work on virtually any kind of plastic reservoir (hard or soft) and are insensitive to the type of fluid being used or to the temperature (down to  ~ -5oC) (Figure 6). Thus, despite their disadvantages, roller pumps still trump centrifugals because it easily possible to reliably and dynamically know the flow being delivered to the patient – and that is critically important.

This is an example of an area where expertise in cryonics, related to the application of extracorporeal  medicine, is critical. Medicine does not smoothly map onto cryonics, and this true not just in extracorporeal medicine, but across the board.  A consequence of this is that if you try to take a physician, a surgeon, a perfusionist, or a paramedic, and simply “dump” them into the cryonics arena, they will typically make very serious errors. This is to be expected, because any specialized area of technology, be it medicine, engineering or computer programming, has its own unique operating parameters and its own unique set of specialized requirements and skills. Cryonics is properly a highly specialized branch of medicine, just as are neurosurgery and cardiac surgery. It is grossly unfair to both cryonics, and to medical professionals, to behave otherwise.  I think that Maxim both refuses to believe this is so, and finds it highly offensive, neither of which change the reality of the situation.

Posted in Cryonics Technology (General), Medicine, Perfusion | 3 Comments

Response to Maxim’s Rant about Automation in Cardiopulmonary Bypass

By Mike Darwin

“Off with their heads!

Off with their heads!”

That’s what Melody Maxim says!

The Queen of Perfusion?

No, that’s just a delusion

And once you read this

There will be no confusion!

A creature right out of Alice in Wonderland, Melody Maxim is the Red Queen of Perfusion, condemning any and all to death, who dare to disagree with her.

Eine Kleine Nachtmusik

I loathe the use of the ad hominem in arguments, and the proof of this is that I rarely use it (and much of what I’ve written is on-line, so this statement can be easily checked). I feel this way about it because I’ve so often had it used on me. My secondary school years, particularly the first two, were horrible. They took the concept of bullying to a whole new level. My response to this was to keep as low as profile as possible, and to go out of my way not to get beaten up – either verbally or physically. It didn’t work. While I can’t say I was grateful for the experience, I did learn a lot from it, not the least of which was the understanding that there isn’t just one type of “bully” or “harasser.” They come in a variety of phenotypes and they are often motivated by very different things.

I also learned that the old axiom about sticks and stones and broken bones is a bold faced lie. Words can and do hurt, and it is a disservice to tell people being injured by them that they are of “no consequence,” or should be allowed to “roll off their backs like water off of a duck’s back.” And so we come to Meoldy Maxim, and the others like her who persist in attacking and threatening cryonicists. There is no reasoning with her, and even honestly agreeing with her on many of her criticisms regarding the poor standard of care in cryonics has no effect. In fact, even having made many of the same criticisms, both before and after her entry into cryonics, has no effect (for example see: http://www.network54.com/Forum/291677/thread/1233270318/Request+for+clarification+from+Melody+on+disagreements+with+Mike+Darwin+%28loose+thread%29).

Two of her favorite hobby horses to ride on her attacks on cryonics are that cryonics has never used extracorporeal medical technology, and that cryonicists misrepresent themselves as medical professionals. I, and many others in cryonics have been the subject of countless electronic and media articles over the years. These reports usually open with, or quickly get to, “the fact that the people performing these (cryonics) procedures are not doctors or, in most cases, nurses…etc.” The reporters writing these stories do this for two reasons: 1) because they were told what the qualifications (or more properly, the lack of medical/professional qualifications) of said staff were, and 2) because it makes cryonics seem less credible and more controversial. I have never misrepresented myself as other than what I am, and aside from that being something that seemed the moral and commonsense thing to do at the time, it has also proved to be especially wise in this era of collapsed privacy, and easy access to all manner of information via the Internet. So, it is actually possible to check on these things, and if you want to fess up the money, you can retrieve those countless newspaper and magazine articles.

But that is not satisfactory to Maxim:


“I think it damages the credibility of cryonics organizations, to represent staff members as medical professionals when they are not. In fact, I am often tempted to argue it is a form of consumer fraud. It doesn’t take much common sense to  know that people interested in cryonics, who view photos of people appearing to  be performing surgical procedures, while dressed up in medical garb, and being  referred to as “surgeons,” “perfusionists,” or other specific medical  professionals, will be left with the impression these people have the  appropriate qualifications, to be referred to as such. It would be extremely difficult for me to believe that the people behind those photos and case reports were not fully aware of this.”

Yes, it is certainly true that cryonicists have referred to the positions on the cryopreservation team by the medically descriptive names, such as “surgeon” for the person who performs, well performs what? Cannulation? No, that’s a medical term, too. And it is equally true that mostly the folks at Alcor and BioPreservation (when it existed), wear surgical gowns and that we always used scrub clothes, drape sheets and other “medical attire” and accoutrements. We did so and do so for the same reason that medical professionals do – to protect the staff, as well as the patient from pathogens. Sometimes, we don’t use surgical gowns, because the risk of infectious disease (Hepatitis C with other viral co-infection) makes biohazard-grade Tyvek coveralls a better option. Maxim wants cryonics to be completely staffed by medical professionals and to use only FDA approved medical technology and devices, and yet she vehemently objects when, in fact, a Board Certified perfusionist is “pumping the case” and a licensed physician is performing the surgery and a licensed scrub nurse is handing off the instruments and a respiratory therapist is operating the blood gas equipment.

For myself, I’d be fine with assigning made-up, or de novo names to each of the people who perform the tasks of scrub nurse, surgeon, circulator, perfusionist… as well as creating new garb. The fact is, it never occurred to me or to Jerry Leaf to do so – we were too busy trying to apply medicine to cryonics. In the 1920’s and ‘30’s one of the greatest surgeons who ever lived, Alexis Carrel (he developed the definitive technique for anastamosing severed blood vesels, thus making transplantation of solid organs possible) fancied the garb you see in the photo below. Carrel believed that sunlight corroded the brain, and that that was why, “The world’s great civilizations have formed far above the equator, where there is much less direct sunlight than in tropical regions.”

Alexis Carrel with an assistant operating his black operating room, dressed in his black surgical garb at the Rockefeller Institute in the first decades of the 20th century.

But not only wouldn’t that satisfy Maxim and her ilk, it would simply give her (and the rest of the world) additional ammunition to label cryonics a cult. And even I have to admit that the picture of Carrel above, is pretty kooky. So, we come to at least the second lesson about a bully like Maxim, and that is that you are damned if you do, and damned if you don’t. Use medical equipment and wear protective medical garb (which also happens to be sterile and very low in shed particulates) and you are perpetrating consumer fraud. Fail to do these things and you are a quack. It matters not at all that you have consistently, and for decades, carefully explained that you are not Board Certified medical professionals. And if you do, in fact, follow Maxim’s suggestions and, for example, hire the very per diem perfusion service she her self suggested be retained, well, then you are still an incompetent fraud trying to bilk an unsuspecting public of their money.

Harm does not just involve the public’s reaction to these posts by Maxim, and others. It can and does involve the devastating impact on the people within cryonics, as well. Men who are professionals, who I interface with in critical care medicine, and who have seen the material Maxim, et al., have written, have remarked that they would never get involved in cryonics, if for no other reason than that they would not want their current or future employers seeing things like “fuckpipe,” “animal torturer,” or “murderer” come up on a Google search of their name. In a world full of competent people looking for jobs, which one would you pick if your job was on the line for the downstream consequences of making the ‘wrong’ choice in an employee, strictly from a PR standpoint, and leaving competence out of it. Just log on to Cold Filter (http://www.network54.com/Forum/291677/) and look at Maxim’s rants. Yes, those posts are certainly going to make it a lot easier for the medical professionals she claims she wants to populate cryonics, to get involved.

What makes her approach particularly vicious is that virtually from the day cryonics was born, it has been impossible to get those kind of professionals involved on any consistent, reliable or adequate basis, because the majority of the population thinks the idea of “freezing dead people to be brought back to life in future centuries when they can be cured” is barking mad. And they still do. And that attitude had (and has) nothing to do with how cryonics is practiced, then or now. Certainly, progress has been made, in that I no longer have people faint or vomit when the idea is proposed by one of its practitioners (things that happened to me twice in the course of polite party conversation in the 1970s), and there is no longer the rabid response of nihilistic young ecofreaks, “that the world will be destroyed by overpopulation from cryonics if it works and how dare we…” The world is already well on its way to destruction by overpopulation, completely absent any help from cryonics; sanitation and vaccination were more than enough to do the job.

One of the many things I’ve learned from all of this is that peoples’ opinions about cryonics are shaped to an astonishing degree by rumors and hearsay. This is so because cryonics is not accepted and is not a topic of mainstream coverage in the media, or in medicine or government, and therefore it is also exempt from the corrective mechanisms that are normally present in these spheres.

If someone were to credibly, for instance, say that Brad Pitt was a Satanist (i.e., not the National Enquirer), an entire set of powerful mechanisms stands ready and waiting to both refute and punish them, if what they say is both taken seriously, and is not true. And while most average citizens don’t know these mechanisms exist, they do know that such statements are not to be taken seriously unless some sort of consensus is present in society. Also, and this is very important, the average person actually (usually) cares enough to ask that critical follow-up question, “How do you know he is a Satanist?” He cares, because if true, that’s an incredibly socially valuable piece of information to him, personally. He can then tell his friends at work, his wife and his golfing buddies, “Hey, did you know Brad Pitt is a Satanist! Yeah, there’s a shocking video on Youtube, made by one of his former nannies, of him sacrificing little African babies in a Satanic Ritual!”

Of course, if there is no Youtube video, or other credible evidence, such remarks will be dismissed as coming from a nut, or some kind of lunatic who has a fixation on Brad Pitt. By contrast, cryonics is in the unfortunate position of already being considered suspect, and cryonics is also of no consequence to 99.99…% of the population. Therefore, negative remarks further degrading its reputation count vastly more.

When I visited Dearborn Village outside Detroit, MI many years ago, I got lucky, because a Lincoln Scholar from the University of Illinois was giving a guest lecture in Lincoln’s relocated courthouse, which is part of the Village campus (Henry Ford did all this in homage to Edison, Lincoln, and others he admired). The topic of his lecture was Lincoln’s law practice, and his legal experience as a rural lawyer. As it turns out, the vast majority of Lincoln’s cases were libel and slander torts. The reason for this was that people at that time and in that place, had almost no assets. They had few chattels, and even less cash. The nature of the communities in rural Illinois was such that they were both small and geographically remote from each other. Farmers, craftsmen and professionals would thus service a large, but sparsely populated area. All these people had were their reputations (and no, or very little savings to fall back on); and this at a time when much more mattered than if you were competent. If you were said to be an adulterer, a Catholic or a Jew, or any of a thousand other ‘bad’ things, well, you were very likely to find yourself with no livelihood. Scandal meant something in those days, and it didn’t have to involve having 6 mistresses, or engaging in endless nights of cocaine and prostitute filled revelry. All that was required was to be morally purblind or, heaven forbid, even a little dishonest.

That is what is happening to cryonics, and I know this to be so when a respected cardiac surgeon in INDIA, who knows me only via the web, drops me a note saying, “Mike, I was under the impression you guys in cryonics used CPB technology…what is this all about?” At least he asked. Most wont.

The Bard said it best in Othello:


Good name in man and woman, dear my lord,
Is the immediate jewel of their souls.
Who steals my purse steals trash; ’tis something, nothing;
‘Twas mine, ’tis his, and has been slave to thousands;
But he that filches from me my good name
Robs me of that which not enriches him,
And makes me poor indeed.”

Response to Melody Maxim

In a message dated 1/23/2011 2:00:09 A.M. Pacific Standard Time, owner-cryonet@cryonet.org writes:

Message #33264
From: “Melody Maxim” <perfusion333@comcast.net>
References: <20110122100001.21427.qmail@rho.pair.com>
Subject: In Response to Mike Darwin’s “Automated Data Collection” Post…
Date: Sat, 22 Jan 2011 15:31:09 -0500

MM: It is absurd for Mike Darwin to maintain that cardiovascular perfusion is “very simple to automate compared to some of the unbelievably complex and exacting manufacturing processes (he’s) seen automated.. It can be surprisingly difficult, even if you have you have experts, and enormous computing power at your disposal.” [sic] (*Note: Mr. Darwin refers to cardiovascular perfusion as “cardiovascular bypass,” terminology that might be confusing to some, as indicated by Perry Metzger’s Cryonet response to Mr. Darwin, in which Mr. Metzger appears to be asking if Mr. Darwin is referring to automating an entire cardiovascular surgical procedure. (Cryonet message

MD: First, if you want to have a respectful technical dialogue you should, a) be sincerely interested in a dialogue, and b) treat your correspondent respectfully. Words like “absurd” and “arrogant” don’t work anywhere in any forum of debate or discussion; with the possible exception of politics and religion – and neither are under discussion here. If you can’t do that, you will either need to go elsewhere, or you will get no response from me, or most others here.

While it is technically correct to use the words ‘cardiovascular perfusion,’ (since the circulatory system may also properly be referred to as the cardiovascular system), the more correct terminology is ‘cardiopulmonary perfusion.’ However, even t hat term is a bit of a misnomer, because during much of the interval when perfusion is carried out during cardiac surgery (its most common indication) the pulmonary circulation of the lungs is, in fact, poorly perfused and usually not perfused at all. This is because the patient’s heart is arrested with cardioplegia (to allow the surgeon to work on it with greater ease and to spare its high energy reserves) and the right ventricle is unable to perfuse the pulmonary circulation. The lungs do have a separate parenchymatous circulation, and this does continue to be perfused in most clinical settings where CPB (cardiopulmonary bypass) is employed. However, under low flow/low pressure conditions, lung parenchymal perfusion may be absent, or reduced to trickle flow.

MM: It’s nonsensical to assert that something “very simple” is at the same time “surprising difficult,” even in the hands of experts with unlimited  technological resources. Even more than that, it is preposterous to compare the manufacturing of a specified component, or device, which requires the same, precise, repetitive steps, time-after-time-after-time, to the perfusion of human beings.

MD: Yes, it would be nonsensical to assert those things if I had said what were being attributed to me. But in fact, I did not say “unlimited technological resources,” because, to the best of my knowledge, no one has those at their disposal; and I did not compare automating CPB to ”the manufacturing of a specified component, or device, which requires the same, precise, repetitive steps, time-after-time-after-time.”

The difficulties of automating CPB relate to its dynamic nature, the complexity of the controlling decision tree required, and to the ‘dynamic rates of change’ nature of many of its features – the latter of which are addressed in mathematics by the calculus. Having said that, CPB is, in fact, fairly straightforward to automate (within limits) when compared to other complex procedures that have been automated. A wide range of manufacturing processes involve similarly nettlesome problems with regard not only to change in pressures, volumes and flows, but also with respect to the rapid addition and removal of heat (again, a rate of change of problem). And while many of these processes do involve very uniform systems, some do not.

Landing jetliners, contrary to MM’s assertion, is in fact a good example of this, because this task is every bit as complicated as perfusion, if not more so. Computerized control of landing requires enormous integration of data from multiple control surfaces on the aircraft under widely varying conditions; and in fact, not only widely varying conditions, but dynamically varying conditions. With automation, it is possible for aircraft to do things that no human pilot ever could.  For example, at airports equipped with category IIIc ILS (instrument landing system) aircraft can use their ‘autoland’ function to land in zero visibility conditions.1 That’s mind blowing when you think about it: 500 lives hurtling at 200 miles per hour toward a runway that no one can see, with no pilots touching the controls, and with the safe bump of landing gear on the pavement being the first clue that the ground has been reached. Under such conditions, rates of change problems become paramount, just as they do in CPB. And, I would be the first to admit that I had absolutely no idea that this would be the case when I set out to undertake this task (in conjunction with others blessedly more knowledgeable than me).

MM: Responding to Mr. Darwin’s automated airplane/perfusion analogy, it doesn’t
matter WHY the wind blows, or WHY the terrain rises, it only matters that the plane must maintain its center of gravity and stay above the terrain. However, it DOES matter why venous return to a heart-lung (perfusion) machine diminishes. Did the patient’s blood vessels dilate, resulting in more volume remaining in the patient, and less returning to the machine? If so, the proper response might be administering vasoconstrictors. Is the surgeon pulling the heart over, so that he can work on the posterior side, temporarily interfering with the venous return to the machine? If so, the
proper response is to temporarily adjust the flow rate, provided that doing so does not result in the patient being inadequately perfused. Has something happened, which resulted in an unexpected loss of blood, from the patient, or perfusion circuit? If so, that situation needs to be recognized and corrected, immediately, and volume must be added to the system, to replace that which has been lost. (This discussion is simplified, and intended to be for an audience of laymen. There are many factors, in regard to both the causes, and the responses, to such a situation.) If the returning volume is suddenly depleted, does the computer have discussions with the anesthetist and the surgeon, to determine the cause of, (and, therefore, the proper response to), such a situation? This is only one example of MANY issues, which perfusionists must respond to, on a case-by-case basis; a situation that precludes the use of fully-automated perfusion systems. There is nothing in the perfusion process, similar to the precise manufacturing of components, or devices, no matter how complex that manufacturing might be!

MD: Now, we are onto the real issues here. As a matter of fact, it does matter WHY the wind blows and WHY various control surfaces (and the aircraft’s position) respond as they do, and for much the same reasons as changing physiological parameters matter in CPB. If descent is a little faster than predicted, is it because the ailerons are not responding appropriately, the air density is unexpectedly low (low barometric pressure), or the engine speed is inadequate - or because any or all of these values are being reportedly incorrectly?

This is what the ‘control center’ (formerly the engine room) of a contemporary state of the art cruise ship or large cargo vessel looks like:

Engineering control room of a modern, computer controlled cruise ship (L).

Virtually every function of the ship is automated and requires ‘only’ intelligent oversight. As is the case in CPB, many of the systems within the ship are in continuous, dynamic interplay with each other – as is also the case in living organisms. These systems are increasingly being merged – with water distillation for bathing and cleaning being integrated with heat exchange operations, such as cooling the generators that provide power, not just for the ship’s electrical systems, but for the azipods[1] that are now rapidly replacing propellers and diesel engines. I could go on for pages about large ocean vessel automation; I’ve been all through these kinds of vessels, and sat for hours on the Bridge and in the engineering (or control room: engine room is passé). In many ways, these systems dwarf automation in aviation because pretty much the entire ship’s systems are now under computer control – the generators, electrical load management, azipods, heating, cooling, water and waste processing, are dynamically controlled by computers.

Since these systems are increasingly integrated and interdependent for increased energy efficiency, they behave much like physiological systems. For instance, if you are moving waste water around to treat it for discharge and/or reprocess it for cooling the generators’ engines, you will likely affect the CG of the ship, as well as its hydrodynamic behavior. Of course, sea conditions can do this, as well as fuel use, movement of cargo or ballast, and so on. The computerized systems integrate all this data and seamlessly adjust the ship’s stabilizers, azipods and other control mechanisms to compensate – as well as dynamically adjust the ballast. Each seagoing vessel also has a transponder which continuously broadcasts a unique identifier number, which includes the vessel name, type of cargo, destination, course and current heading (among other things). All of this data is displayed on flat screens on the Bridge in real time, and the on board computers can and do, dynamically adjust the course to avoid collisions.

Cruise ships, in particular, are very sensitive to any disturbance which could cause passenger discomfort. They also have a highly mobile cargo, massively complex infrastructure (they are actually self contained cities, much like long-haul star ships) and they consume enormous amounts of power for refrigeration and HVAC. All of this is managed by process control systems that dwarf CPB in their complexity, and in their criticality to human life.2 Spend a few days with unfettered access on a state-of-the art container ship and cruise ship (the latter should be at least Panamax class, and preferably built within the past 10 years).  Each is impressive in its own unique way, and each represents a pinnacle of automation and technological achievement that I think very few people understand exists.

Similarly, the Bridges of large, state-of-the-art cargo ships are almost completely automated and typically require the oversight of no more than 2 men at one time – an incredible feat of programming and engineering. And when I say oversight, I mean just that – mostly the First Officer and Captain sit and do paperwork. The degree and sophistication of automation required to operate such a ship, largely absent human intervention, dwarf the automation of CPB at a comparable level of oversight.

Automated Bridge of a contemporary state-of-the-art large container (cargo) ship.

Changes in physiological parameters can indeed have multiple causes, and may in fact occur because several very different mechanisms are at work at the same time and are interacting with each other! Arterial pH is a fairly straightforward example to use. If a patient’s pH declines to a level deemed unacceptable, it could be due to any of the following things (at a minimum): inadequate ventilation (which in turn could be due to inadequate O2 delivery and/or inadequate CO2 removal by either the gas blender or due to failure of the oxygenator), global hypo-perfusion, regional hypoperfusion, administration of large volumes of low pH parenterals (typically IV fluids), and so on. If you want an automated system to control patient pH dynamically, that system has to be imbued with both the tools and the intelligence to discriminate amongst the possible causes, determine which causes are operational at the moment, and act to intelligently correct them.

Such correction may entail more than one intervention since the ’cause’ of a drop in arterial pH may be due to several causes – although usually this is not the case. And this complex interaction becomes greatly amplified when it is understood that pH effects vascular tone, and thus can cause vasodilatation, resulting in decreased mean arterial pressure (MAP, blood pressure), or the converse. Any robust automated system has to be able to look at the ‘big picture’ and make the correct adjustments. These things I understood very well when I began the effort. However, what I did not understand was the ‘invisible experience’ that most humans have when it comes to dealing with dynamic systems where rapidly varying (and recursive) rates of change of are involved. This is hard for me to explain, but I’ll do my best.

When I first sat down with a couple of clinical perfusionists and began to work on this project, the thing we all ’missed’ at first, is that you cannot just specify ‘high’ and ‘low’ numbers for things like arterial and venous pressures, or for arterial flow, at which point the machine will ‘act’ by adjusting said pressure or flow to the desired value. In other words, you cannot just program in ‘alarm limits’ to which the machine will respond. It turns out that most such corrections to physiological parameters are made more or less unconsciously, and are based to a significant degree on the observed rate of change, and even on the shape of the curve of the rate change!

Central venous pressure and pulmonary artery pressure proved particularly difficult to control because they must be kept low (in absolute terms), there is very little range to work with, and they may vary based upon a number of interacting factors, some of which can change with incredible rapidity (i.e., the venous return line from the patient becomes suddenly occluded). If you wait to intervene until some ‘target’ number is reached, you will almost always over- or under-shoot, and the same will be true of subsequent efforts to correct the pressure and return it to the desired range: thus, a vicious circle of positive feedback results. As it turns out, this is a common problem in process control, and there are program algorithms to deal with it. The standard algorithm used for process control is something called PID, which is short for Proportion/Integral/Derivative control.3 This means that in, say, controlling pump speed to maintain a target perfusion pressure, the system will look at three things: How far you are from the target pressure (‘proportional’), how fast to incrementally change the pump speed to approach the target pressure (‘integral’), and how fast the target pressure is being approached (‘derivative’).  The art of process control is in tuning the values of these three parameters so that targets are reached and maintained as quickly as possible, and without overshoot.

Thus, I learned that a lot of what constitutes ‘gaining experience’ in things like perfusion, or piloting aircraft, is learning to apply corrections that, while they may seem ‘set point’ driven, are, in fact, very complex responses to equally complex changes in a dynamic system.

MM: Perfusion IS automated, to a large degree. Perfusionists can program their machines to respond to various parameters, in a variety of ways. For example, the machines can be made to automatically adjust flow rates, in response to pressure; or to turn off a pump and clamp the patient lines, in the event of inappropriate pressures, or air in the lines. But, what happens after that?

MD: I would hardly consider such simple control any kind of high order automation. Here we touch upon another issue: the degree to which you wish to automate perfusion or perhaps more accurately, the scope of automation that is being pursued. Nowhere in what I wrote did I suggest (or even imply) that the level of automation we were pursuing would replace a knowledgeable person. In fact, I was at pains to point out that this was not the case; at least not with the resources (or objectives) at our disposal 15 years ago! While our objectives were indeed daunting, they comprised only a small subset of the requirements that would pertain in an operating theatre, where ’perfusion’ might consist of a routine CABG, a double valve replacement, or resection of a brain aneurysm under deep hypothermic circulatory arrest.

What we were aiming for (and largely achieved) was a system that could initiate CPB in an animal (dog) after ~15 min of normothermic circulatory arrest, restore both cardiovascular and basic metabolic homeostasis (pH, A&V blood gases and regulate blood glucose), and induce hypothermia to a pre-specified degree. An additional (non-CPB related) requirement was the controlled and feedback-driven administration of a number of cerebroprotective drugs – some of which perturbed MAP.

MM: Someone, who knows how to assess the situation, and produce the proper response, must be operating that machine. I find it quite arrogant, for Mr. Darwin to claim he has tried to automate perfusion systems and has found it difficult. Does Mr. Darwin think he compares to the scientists, perfusionists and engineers, involved in equipment development, with the major manufacturers of perfusion equipment? While I’m sure Mr. Darwin has toyed with primitive perfusion equipment, at cryonics facilities, he is not a perfusionist, or an engineer, and he certainly does not have resources
comparable to those of companies, which specialize in perfusion equipment, such as those mentioned here: http://www.perfusion.com/cgi-bin/links/default2.asp?tree=558

MD: As I pointed out earlier, our efforts were undertaken 15 years ago. Having said that, yes, we were in fact working with state-of-the art equipment where that was possible and appropriate. For instance, we did not try to build our own gas blenders, blood pumps, reservoir level sensors, or ultrasonic air bubble detectors. Where it is possible to use a developed and reliable commercial product, only a fool or a very poor (and/or desperate) person chooses to do otherwise. We were neither that foolish nor that poor. We used costly state-of-the art LabView data acquisition and process control hardware and software as opposed to trying to do our own programming or solid state electronics design.

Automating basic cardiopulmonary bypass in the late 1990s at 21CM. Today, the process control and computing equipment occupying the panel rack at the left of the photo above would fit easily into a space about the size of two laptop computers – and still have capacity to spare!

However, it should be remembered that in much of the world people are desperately poor, and they must ‘engineer on the fly’ if they are to survive.4,5 They often do so, and in fact, more often than not they do so with stunning efficacy. I’ve seen plastic soda bottles used as re-useable re-breathing reservoirs in patients getting O2 therapy, soda bottles used with aquarium frits as humidifiers on ancient (but working) ventilators, and CPB performed where the same blood filled circuit and oxygenator (sans filter) are used on 3 successive patients (with compatible blood type and cross match). Are these things desirable? Of course not, and they carry risks that would be completely unacceptable here in the developed world, where I happen to be at the moment. But, to patients who are confronted with otherwise certain death, and to their treating physicians who have no other alternative, these kinds of compromises save lives – a lot of lives. Similarly, in most Third World countries, many disposable medical devices are reprocessed and reused – often many times – with little or no downside. Disposable oxygen masks, nasal cannulae, O2 conductive lines, suction lines and canisters, and many more devices can be safely and reliably reused providing good protocols for doing so are in place, and well trained people inspect the end product.

As to interfacing with the manufactures of perfusion hardware and disposables, I was lucky to count as a colleague the then CEO of Gish Biomedical, who was incredibly generous with disposable components, and who provided access to his engineers at no cost during this project. Ditto Sarns. These companies were interested in what we were trying to do and they provided as much informal support as I could have wished to have. In fact, it was from these people in industry that I was first acquainted with the real problems that stood in the way to developing this technology, problems I didn’t understand, because I lacked their enormous expertise and, more importantly, experience with the commercial and regulatory environment. While I lacked these things, I didn’t lack the wisdom to go in search of them elsewhere.

Before FDA regulation of medical devices (which is comparatively recent), the barriers to doing something like automating CPB to the extent we trying to achieve would have been far lower, if for no other reason than that the interface of hardware, software and drug delivery components would not have been subject to FDA vetting.6 This raises the cost of approval considerably. Additionally, the then (and now) current market for in-field CPB, using automated systems, is virtually non-existent. As was pointed out to me, even if 20,000 cases per year presented (about 10% of the sudden cardiac death population in the US at that time) it would still be uneconomical. And indeed, when 21CM ultimately began licensing discussion with Pharms for the cerebroprotective regimen we had developed, the projected marketplace, when considered in the context of the certain regulatory approval costs, was deemed way too small.

While 150,000 or even 250,000 patients/year may seem like a lot, it really isn’t when you consider that the complex technological platform of multiple novel drugs, and sophisticated hardware and software would only be used, on average, ONCE by each patient who needed them. Development and regulatory costs for drugs are now so high that big Pharma has concentrated its efforts primarily on drugs that will require extended, or preferably life-long use (i.e., psychiatric drugs, dyslipidemia drugs, antihypertensives…)  and on drugs that will command large reimbursements because they deliver comparably dramatic results (such as Gleevec and other targeted ‘molecular therapeutics’ for cancer).7

MM: Darwin wants to argue that such automation could require less-skilled personnel, something I find disturbing. Someone who does not routinely assemble and operate perfusion equipment is very unlikely to be able to assess, and correct, problems that might occur with an automated-system failure. Would Mr. Darwin like someone who has memorized the contents of a dozen aviation textbooks, but never flown an airplane, to be sitting in the cockpit of his commercial airliner, when the computer goes out? I find his argument for “knowledge without reflexes” being “sufficient,” (in regard to cardiovascular perfusion and flight), to be absolutely ludicrous.

MD: Given the statement above, Maxim may soon have to give up flying altogether,  because not only are most commercial jetliners piloted most of the time by computers, the latest generation of high performance aircraft cannot even remain in the air without them – pilot or no pilot. The advent of highly reliable automation has led to the design of aircraft that are inherently unstable. In other words, these aircraft must be provided with continuous and very complex adjustment to their control surfaces to remain airborne; so called fly by wire (FBW) control. Examples of such aircraft are the F-117 Nighthawk and the B-2 Spirit flying wing.

The Grumman X-29A is an example of an extremely inherently unstable aircraft whose design elements may soon be adapted for civilian use.

Piloting inherently unstable aircraft is so complex and difficult a task that human beings cannot do it. High performance aircraft that have FBW controls (also called CCVs or Control-Configured Vehicles) may be deliberately designed to have low, or even negative aerodynamic stability in some flight regimes; in which case the rapid-reacting CCV controls compensate for the lack of inherent stability. The use of CCV technology allows for a large weight reduction in the aircraft by eliminating most of the hydraulic and electromechanical controls formerly necessary, and it dramatically reduces the workload and fatigue of the flight crew. Yet another powerful advantage in this era of skyrocketing fuel prices is that CCV technology increases fuel efficiency by optimizing control of the aircraft and by eliminating ‘pilot induced oscillations’ which negatively impact fuel consumption. So powerful is CCV, that an entire book has been written credibly suggesting that pilot Sully Sullenberger’s ‘miraculous’ emergency landing of that US Airways Airbus A320 on the Hudson river after it was disabled by geese entrained in the engines, was not so a much a miracle as an artifact of CCV technology (see Fly By Wire: The Geese, the Glide, the “Miracle” on the Hudson by William Langewiesche)! An interesting interview with Langewiesche on his book is available here: http://www.amazon.com/Fly-Wire-Geese-Miracle-Hudson/dp/0374157189.

Coming down the pipe are the Intelligent Flight Control System (IFCS) which NASA-Dryden demonstrated as workable in 2002.8 The IFCS allows the aircraft to continue in flight and lad safely even after serious damage to the aircraft control surface or airframe damage would normally render the flight control system’s worthless, or put less politely, no longer controllable by a human pilot. IFCS uses neural network technologies with state-of-the-art control algorithms to correctly identify and respond to changes in aircraft stability and control characteristics, and immediately adjust to maintain the best possible flight performance during such failures. The neural network computer and software ‘learns’ the new flight characteristics of the damaged aircraft in real time, ‘helping’ the pilot to maintain or regain control and prevent a catastrophic failure. This system has succeeded in landing severely damaged aircraft in testing.

As to Maxim’s statement that my “argument for ‘knowledge without reflexes’ being “sufficient,” (in regard to cardiopulmonary perfusion and flight), to be absolutely ludicrous,” the answer is, “Not at all.” I assume that Maxim has not pumped a case in some time, in which case she is just such a person as I describe; she has knowledge, but not reflexes. The same would be true of a race car driver who has not raced in 6 months (or maybe less!) or a pilot who has not flown for a year. Maybe one of the best examples I can offer is that of a ‘retired’ gymnast or ballerina who teaches these arts. Physiological limitations related to aging make the careers of these people extremely short. In the case of gymnasts, their careers are pretty much over by their early to mid-20s. They have the knowledge, but they no longer have the ‘reflexes,’ or even the physical ability to perform. However, they make superb instructors, and they can detect errors with great speed. But more importantly, they have the ‘meta-knowledge’ that the novice does not have. That is what I meant by ‘knowledge without reflexes.’ I know very well that I would experience an unacceptable failure rate if I were to walk into an OR and try to do CPB on a research animal under demanding conditions after 10 years away from doing CPB at all. Indeed, I would want to start out slowly, and partner with an up-to-speed perfusionist before I ‘soloed’ again. I assume the same would be true of a clinical perfusionist who had long been away from the OR.

The advantage that a well automated CPB system provides is that it allows the skilled person to focus on the use of his high order knowledge without being occupied with housekeeping tasks. In fact, it was for just this reason that automated piloting and landing of jetliners was developed. This technology was not developed in order to let pilots wander about the cabin chatting with passengers while the plane was being landed. Nor was it developed to cover the contingency that the pilot and copilot might both be dead or disabled, or that the pilot and co-pilot might be in a particularly compelling discussion about scheduling, and allow the aircraft to fly blindly on past its destination by hundreds of miles, as happened recently. Rather, it was developed for just the reasons I’ve laid out here.

Our incentive to develop this technology at 21CM was that the interventions required for restoring homeostasis, rapidly inducing therapeutic hypothermia after prolonged cardiac arrest and simultaneously administering over a dozen different drugs, were simply beyond the ability of humans – any humans, to carry out reliably. There are some things people can’t do, even in medicine, and as a consequence we see the advent of robotic surgeons, IV fluid administration systems that can shape the curve of a drug dose and impose periods of ‘ramp and soak’ that would require the full time attention of a human, and still be done badly. There are even programs that alert physicians and pharmacists to medications conflicts as they write prescriptions, because humans are miserable at remembering such information.

Perhaps the best example is one of the simplest. With the advent of mild therapeutic hypothermia (MTH) as the internationally recognized treatment of choice for post cardiac arrest encephalopathy, it is now necessary to impose ~3 deg C of hypothermia with very tight control of temperature for 12-24 hours post-insult, followed by controlled, slow re-warming to normothermia.9,10,11,12 Note that while there is only one parameter to control in this system (temperature) – humans are horrible at it – even if you set one person full time on these two tasks. It also turns out that simple ‘set point’ systems, like those present in most medical cooling blanket systems which use feedback from the patient in the form or rectal or esophageal temperature, are also awful at tight temperature control. Such systems routinely over- or under-shoot the required temperature, and as a consequence, much more sophisticated devices, such as the Arctic Sun (external) and the CoolGuard (intravascular) clinical hypothermia systems which use complex algorithms to impose and maintain MTH, and carry out re-warming, have been developed, and are finding clinical acceptance.13,14,15,16

Humans are simply incapable of the precision process control required for things like imposing artificial temperature homeostasis in critically patients without the assistance of automation.

MM: Mr. Darwin’s remarks about a market not existing, for automated perfusion,
resulting in “no economies of scale…that further drives up the price and  drives down the reliability of any system you do develop,” is just as ridiculous as most of his other observations and speculations. The perfusion disposables I used two decades ago, cost approximately $1,600; today, the same disposables are around $500. I’m not a financial expert, but the machines, themselves, seem not to have increased more than that due to ordinary inflation. If there has been an increase, it has probably been due to the developments in the computerization/automation features! Salaries also seem not to have risen, other than increases due to inflation, over time. Never before has perfusion been so technologically-advanced, reasonably-priced, or safe. It is much more likely that heart surgery will eventually be performed, without the use of perfusion, than with the use of fully-automated perfusion, as evidenced by an ever-increasing number of
“off-pump” procedures. (Of course, this has nothing to do with cryonics. Heart surgery can sometimes be performed, without the use of perfusion, but the vitrification of human bodies cannot.)

The tipping point as to when a technology becomes cost effective and viable to use is one upon which fortunes are made and lost – and not just in medicine. Fully automated CPB will require the development of very sophisticated AI and robotics; and I don’t see that as being around the corner. As MM points out, in the 15 years since we undertook our pilot project, there have been incremental (but important) advances in the ‘automation’ of CPB – but these are almost exclusively concerned with discrete safety issues, as opposed to a more global management of the integrated procedure. Personally, I think perfusion would benefit from a far higher degree of automation, just as the airline industry has. People don’t do well at boring, repetitive tasks, like steering a jetliner (continuously) across the country. It’s better and safer to use them for what they are still currently the best at – meta-level, high order judgment and reasoning. Of course, when a jet liner goes down, it is big news and many people die very publicly and at once. Errors in the OR are not such big news…

Beyond that, in-field automated CPB is currently a product in search of a market that can enable and sustain it. The development of such a market will (IMHO) likely be incremental, and be driven by things like MTH, the approval of effective drugs for post-ischemic brain rescue, and so on. When it becomes clear to a broader cross section of clinicians and business people that a lot of lives can be saved (or enough), and that there is money to be made, then such technology may be developed. Still, arguably the greatest barrier to application of essentially ‘immediate’ in-field CPB is the problem of vascular access. Even with the advent of compact, hand-held imaging devices that allow for non-invasive (or minimally invasive) vessel location, and a growing array of percutaneous vascular access devices, this enabling part of CPB still requires a lot of skill and knowledge which are time consuming to apply, and are also not likely to be automated soon.

MM: The fact that Mike Darwin is one of cryonics’ greatest “superstars” should be quite telling. How many cryonics projects have been directed, on the advice of Mr. Darwin and others like him? How many of those projects were based in ignorance of existing equipment and technology? For so long as people like Mr. Darwin and his peers are considered to be “experts,” in cryonics experiments, there is likely to be nothing more than ample misdirection and false promises. It seems a very small group of self-interested people have made, what could be an interesting scientific experiment, a total sham. (By “self-interested,” I do not mean people who are interested in extending their own lives; I mean people who are primarily interested in maintaining their over-inflated egos and/or bank accounts, by maintaining control of experiments and/or projects, which they are not capable of leading.)

When Maxim writes, “How many cryonics projects have been directed, on the advice of Mr. Darwin and others like him? How many of those projects were based in ignorance of existing equipment and technology?” she should put up or shut up. How about a list of these projects that I have directed, or advised be undertaken, and that have demonstrated such ignorance, and proved so useless? Note, I am not asking for a list of such projects by ‘others like me,’ but rather, of projects for which I have been personally responsible.

I don’t consider myself a ‘superstar’ at anything, and as near as I can tell, that judgment is widely shared (and is especially fervent within) the cryonics community. However, I also don’t think that most of what I did in my years of working in and on cryonics, or biomedical research, was based on ignorance of existing medical technology. Indeed, often the reverse was the case; the technology simply didn’t exist (and often still doesn’t exist), or the medical community, primarily treating physicians (as opposed to drug or device makers), were either ignorant of the benefits of an emerging technology, or were actively opposed to its use (mostly as a result of prejudice and laziness).17 This was certainly the case (and still largely is) with MTH, as just one example.

Willem Kolff’s prototypical dialysis machine: what would Maxim have done to Kolff – especially when consideration is given to the fact that all 17 of Kolff’s first patients died – many as a direct result of complications from the treatment?

In the particular case under discussion, automated (or more properly, partially automated emergency in-field CPB), the then extant manufactures of CPB equipment and consumables were both interested in, and supportive of our efforts, because they all began themselves in pretty much the same way, operating under pretty much the same conditions. Willem Kolff made his first clinical dialysis machine from a custom fabricated enamel pan, a Ford fuel pump (used to circulate the dialysate), unpainted wooden slats and sausage casing (which he passed the patient’s blood through).18 I knew Kolff personally, and there was nothing he would NOT use in medical device fabrication if he thought it was the best item for the job.

C. Walton Lillehei, and his beer tubing and industrial finger pump heart-lung machine, in the early 1960s.

The early days of CPB were characterized by the in-house fabrication of MOST of the equipment that was used and that had blood contact, and a wide variety of common household and industrial items were pressed into service. The first clinically applied bubble oxygenator was made from PVC tubing used in beer breweries (the DeWall oxygenator) and C. Walton Lillehei began the University of Michigan’s stellar cardiac surgery program using this oxygenator, and a hemolysis inducing peristaltic finger pump made by the Sigmamotor Company, for industrial applications!19 It was a long hard road from the beer tubing oxygenator above to the first commercially produced Travenol disposable bubble oxygenator below.

The Travenol DeWall bubble oxygenator marketed in the mid-1960s.

It took the better part of a decade for manufactures to enter the field, like PEMCO in 1961, and a bit later, Dick Sarns, who founded Sarns, Inc. Before that, surgeons, and their nascent perfusionists fabricated their own hardware.  Maxim should read G. Wayne Miller’s superb biography of Lillehei, King of Hearts: The True Story of the Maverick Who Pioneered Open Heart Surgery, ISBN-10: 060980724 , J. Stewart Cameron’s, A History of Dialysis, ISBN: 0198515472, and David Monagan’s, Journey into the Heart, ISBN-10: 1592402658. Monagan’s book is a fascinating exploration of the development of cardiac catheterization and it brilliantly captures how even such recently such developed medical technologies are initiated using commonplace and often crude materials to fabricate truly revolutionary medical devices.

No doubt, Maxim would have stomped down these innovations in their infancy – particularly CPB, since coronary artery bypass grafting (CABG) was inferior to medical management of coronary artery disease in terms of survival until the 1980s, and arguably was not proved otherwise until the Veterans Affairs Cooperative Study of Coronary Artery Bypass Surgery for stable angina was published in 1992!20 Indeed, even the most recent studies show CABG benefits only patients with > 50% stenoses in their left anterior descending coronary arteries (LAD), or a “LAD equivalent” stenosis (> 70% stenoses of both proximal LAD and proximal left circumflex arteries), and in 3-vessel disease in terms of improved survival over medical management. 21,22,23,24 When consideration is given to the fact that the one of the most recent studies of the neurological injury that attends CPB demonstrated a ~50% incidence of both functional and structural neurocognitive injury as a result of CPB,25 one must wonder what Maxim would have to say about her own career, if it happened to belong to someone else?

Even more to the point, both established pharmaceutical and medical device companies are increasingly relying on tiny start-ups and entrepreneurs to do the hard and mostly unrewarding work of finding and developing new products that will actually be viable. Big companies in the US are awful at identifying and developing fundamentally new technologies, and the emerging pattern is for such large companies to either license, buy the new technologies they ultimately market from small start-ups – or to buy the new companies outright.

It’s ironic that Maxim chose to label me, of all people in cryonics, as being ignorant of CPB technology, let alone of failing to use it. As soon as such technology became affordable I used it, and in fact, it was Jerry Leaf and me, who, in the face of considerable criticism from the cryonics community, introduced virtually every element of CBP technology into cryonics that was appropriate (some items, such as large reservoirs to hold CPA solutions were (and are) not medically available). The proof of this is in the case histories published by Jerry and me, and later by me of cases I presided over after Jerry’s cryopreservation.

What is the basis for such an outrageous claim by MM? The answer: there is clearly none whatsoever.

[1] Azipod is the registered brand name of the ABB Group for their azimuth thruster. Originally developed in Finland jointly by Kvaerner Masa-Yards dockyards and ABB, these are marine propulsion units consisting of electrically driven propellers mounted on a steerable pod.

Selected Bibliography

1)    Langewiesche, W. Fly by Wire: The Geese, the Glide, the “Miracle” on the Hudson. Farrar, Straus and Giroux, November 2009, 208 pp, ISBN: 0374157189.

2)    To get some idea of the staggering complexity of the automation required to manage a modern cruise ship you can take a peek inside Royal Caribbean’s ship, Freedom of the Seas, here: http://www.youtube.com/watch?v=YY-3fipCTDw&feature=related. It is due in large measure to this automation that luxury is affordable (and hence possible). Consider that ~$100/day it is possible to dine on gourmet food 24 hrs/day, enjoy live theatre, water sports, and just about every other amenity imaginable, and to do so while at sea! It is passing impossible to find an average hotel room on land in or around any big city for $100 a night – and that does not include food, entertainment, gym facilities, gaming, and excursions – all you get is place to sleep and clean up.

3)    Bennett, Stuart (1993). A history of control engineering, 1930-1955. IET. p. p. 48. ISBN 9-780863412998.

4)    Borst, HG. The hammer, the sickle, and the scalpel: a cardiac surgeon’s view of Eastern Europe. Ann Thorac Surg 2000;69:1655-1662: http://ats.ctsnetjournals.org/cgi/content/full/69/6/1655. Retrieved 2011-01-29.

5)    Bokeria L.A. History of cardiovascular surgery. Moscow: Bakoulev Scientific Center for Cardiovascular Surgery, 1998.

6)    Higgs, R. Wrecking ball: FDA regulation of medical devices. Cato Policy Analysis #235, August 7, 1995. http://www.cato.org/pubs/pas/pa-235.html. Retrieved 2011-01-30.

7)    DiMasi, JA, et al. The price of innovation: new estimates of drug development costs. Journal of Health Economics 22 (2003) 151–185. http://cryoeuro.eu:8080/download/attachments/425990/CostOfNewDrugDevelop2003.pdf.

8)    NASA  – NASA Dryden Fact Sheet – Intelligent Flight Control System: The Intelligent Flight Control System (IFCS) flight research project at NASA Dryden Fact Sheets. Text Size. Grow Text SizeShrink Text Size. 02.13.06 http://www.nasa.gov/centers/dryden/news/FactSheets/FS-076-DFRC.html.

9)   Nolan JP, Morley, PT, Vanden Hoek, TL, et al. Therapeutic Hypothermia After Cardiac Arrest: An Advisory Statement by the Advanced Life Support Task Force of the International Liaison Committee on Resuscitation. Circulation. 2003;108:118 – 121.

10)  Hypothermia after Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med. 2002; Feb 21;346(8):549-56. Polderman, Kees H. “Application of therapeutic hypothermia in the ICU.” Intensive Care Med 2004;30:556-575.

11)  Bernard SA, Gray TW, Buist MD, Jones BM, Silvester W, Gutteridge G, Smith K. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med. 2002;346(8):557-63.

12)  Arrich J, Holzer M, Herkner H, Müllner M. Hypothermia for neuroprotection in adults after cardiopulmonary resuscitation. Cochrane Database Syst Rev. 2009;7;(4):CD004128. Review. PubMed PMID: 19821320.

13)  Haugk, Moritz et al. “Feasibility and efficacy of new non-invasive cooling device in post resuscitation intensive care medicine.” Resuscitation. 2007;75, 76-81.

14)  Hoedemaekers, CW, Ezzahti, M,  Gerritsen , A, van der Hoeven, JG. Comparison of cooling methods to induce and maintain normo- and hypothermia in intensive care unit patients: a prospective intervention study. Crit Care. 2007; 11(4): R91. Published online 2007 August 24. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2206487/pdf/cc6104.pdf. Retrieved 2011-01-31.

15)  Treatment of fever in the neurologic intensive care unit with a catheter-based heat exchange system. Diringer MN. Critical Care Medicine 32: 559-564, 2004.

16) Efficacy and Safety of Endovascular Cooling After Cardiac Arrest: Cohort Study and Bayesian Approach. Holzer M, Mullner M, Sterz F, Robak O, Kliegel A, Losert H, Sodeck G, Ray T, Zeiner A, Laggner AN. Stroke 37: 1792-1797, 2006.

17) Wolfrum S, Radke PW, Pischon T, Willich SN, Schunkert H, Kurowski V. Mild therapeutic hypothermia after cardiac arrest – a nationwide survey on the implementation of the ILCOR guidelines in German intensive care units. Resuscitation.2007;72(2):207-13.

18)  Cameron, JS. A History of Dialysis. Oxford University Press, September 2002, 368pp. ISBN: 0198515472.

19)  Miller, W. King of Hearts: The True Story of the Maverick Who Pioneered Open Heart Surgery. Three Rivers Press; 2nd edition (February 1, 2000), 302pp. ISBN-10: 0609807242.

20)  Eighteen-year follow-up in the Veterans Affairs Cooperative Study of Coronary Artery Bypass Surgery for stable angina. The VA Coronary Artery Bypass Surgery Cooperative Study Group. Circulation. 1992;86:121-130.

21)  Sharma GV, Deupree RH, Luchi RJ, Scott SM. Identification of unstable angina patients who have favorable outcome with medical or surgical therapy (eight-year follow-up of the Veterans Administration Cooperative Study). Am J Cardiol. 1994;74:454-458.

22) Scott SM, Deupree RH, Sharma GV, Luchi RJ. VA Study of Unstable Angina. 10-year results show duration of surgical advantage for patients with impaired ejection fraction. Circulation. 1994;90:II120-II123.

23)  Sharma GV, Deupree RH, Luchi RJ, Scott SM. Identification of unstable angina patients who have favorable outcome with medical or surgical therapy (eight-year follow-up of the Veterans Administration Cooperative Study). Am J Cardiol. 1994;74:454-458.

24) Scott SM, Deupree RH, Sharma GV, Luchi RJ. VA Study of Unstable Angina. 10-year results show duration of surgical advantage for patients with impaired ejection fraction. Circulation. 1994;90:II120-II123.

25)  Knipp SC, Matatko N, Wilhelm H, Schlamann M, Thielmann M, Lösch C, Diener HC, Jakob H. “Cognitive outcomes three years after coronary artery bypass surgery: relation to diffusion-weighted magnetic resonance imaging.” Ann Thorac Surg. 2008 Mar;85(3):872-9.

Posted in Cryonics Technology (General), Medicine, Perfusion | 21 Comments

Last Aid as First Aid for Cryonicists, Part 1

by Mike Darwin

“Recent theorists have argued that humans are genetically programmed to think in story form: stories, they say, are how we best remember the important events in our own lives, how we interpret meaning in the lives of those around us, and how we best remember world events.” – Richard Jewell

Prologue: Let Me Tell You a Story…

The terror in the voice on the other end of the phone was so intense it seemed as though the caller was in the room with me, not over a thousand miles away. I had never spoken with him before, and it had taken extraordinary effort and cleverness on his part to find my phone number. It was 0100; the middle of the night, and his mother was dying. He had emailed me several times in the past with technical questions about cryonics, but other than that, we had had no prior contact. His situation was desperate because, like me, he lived in a small town over an hour away from the nearest Wal-Mart – a pretty good gauge of how far removed you are from the amenities of civilization – and there was little in the way of meaningful help from his cryonics organization.

He wanted my advice and my help on what he could do to improve the odds for his mother, given that she was going to die sometime within the next 12-24 hours. He was fortunate, unusually so, in fact, in that he had two other family members and several close friends who were willing to do just about anything within reason to help him. He, his mother and his sister had been signed up with a cryonics organization for several years and all of them enjoyed reasonable health and seemed in no imminent danger of dying. The fly in the ointment was that his mother had a history of congestive heart failure and neither he, nor anyone else he relied on for advice, understood that that diagnosis in a frail elderly lady is as lethal as any disseminated cancer. With the added twist that decompensation, flooding of the lungs with fluid, and death could occur with little or no warning. It was 1 o’clock in the morning and this man, his sister, and his mother were utterly alone, and utterly unprepared for the emergency that was unfolding in their lives.

He and his sister were unable to reach his mother’s cardiologist, but they did get the family physician out of bed and, as is so often the case in small rural communities, he assessed the situation by phone and offered to come over to see the patient since he was certain to arrive before the ambulance which had been dispatched from yet another small community located 15 minutes further out from the neighboring city (and that could be expected to take at least an hour and a half to arrive). (Both of the neighboring city’s fire department paramedic-staffed ambulances were engaged in other long-distance emergency calls and were unavailable to respond.)

The physician was there within 20 minutes of the call and his assessment was as blunt as it was honest. Their mother was dying, and hospitalization would make no difference in either the duration of the dying process, or its certain outcome. She had suffered another heart attack and now had massive pulmonary edema with large airway flooding, as well as frank hemoptysis (bleeding into her lungs). In medical parlance she was actively dying, and the only realistic course of action was to administer palliative oxygen and morphine and wait for the inevitable. A call was made to the EMT in the ambulance that was en route (who was also head of the volunteer fire department that provided the ambulance service) to ask whether they could leave one of their large oxygen tanks and a portable suction unit for the night, with the physician’s assurance it would be returned in the next few days. The answer was “yes.”

Figure 1: Homemade active compression-decompression CPR device (L) and the Ambu CardioPump (R). The CardioPump costs ~$400.00 US, and is technically illegal to sell in the US. The homemade version (L) costs ~16.00 US, and can be easily made from off the shelf pumping parts available at most hardware stores.

The next six hours of frantic phone calls (including to a funeral home in a neighboring town) and two trips to Wal-Mart did much to remedy the lack of the basics. The funeral director sent his son out with a metal air shipping case (universally and erroneously referred to as “Ziegler cases”). I had asked the son to see if the mortuary could loan him a transport gurney; unfortunately they only had one. I then spoke briefly with the mortician and asked if he had an extra “church cart” which is a scissor-action, horizontally collapsible cart used to move caskets in and out of churches and around the funeral home. He had an extra church cart and agreed to bring it.

Figure 2: A very serviceable expedient portable ice bath (PIB) can be quickly put together using a metal mortuary air shipping container (L), a mortuary “church cart” (R) and ratchet-type nylon tie down straps used to secure motorcycles, or cargo during shipment. The shipper should be lined with a double layer of water-tight plastic sheeting because the shippers frequently leak at the seams!

Upon arrival, the air shipper and the church cart were then paired up using nylon “cargo-style” ratchet straps with S-hooks; converting the air shipper and the cart into an expedient portable ice bath (EPIB) (Figure 2). The trips to Wal-Mart were for an inexpensive, throw-away-type expanded polystyrene (EPS) cooler, half a dozen more rugged picnic chests filled with water ice, two Accu-Rite electronic indoor-outdoor digital thermometers (the kind with the temperature sensor on a long lead wire that is normally placed outdoors), a small submersible-type water sump pump, three yellow plastic Green Thumb (6-1/2”diameter) yellow plastic lawn sprinkler rings, a roll of garden hosing, a large selection of garden hose quick disconnects, assorted other garden and plumbing fittings and connectors, and every garden hose repair kit Wal-Mart had on their shelves.  Also on the list were several packages of disposable nitrile rubber gloves from the pharmacy section of the store and a toilet plunger

The patient’s son said he was “good with his hands,” and in fact one of the one of the reasons he had originally sought me out over the Internet was to ask about the feasibility of making his own version of the Ambu CardioPump for active compression-decompression CPR (ACD-CPR). He had already made a prototype handle for the device, but the type of toilet plunger “suction cup” he had selected would not form a good seal with the chest wall.

I emailed him a set of Transport Data Collection sheets from my BioPreservation, Inc. (BPI) days, as well as some simple and very basic instructions in 16 point type. I pasted in photographs where appropriate, and I also sent along sections from the last version of the BPI Transport Manual. I then spoke at length with the family physician who, while not enthused about cryonics, was genuinely caring, and who agreed to stay with the patient until she experienced cardiac arrest, and then pronounce medico-legal death, and sign the death certificate. He explained that while he was “off” for the next two days with no office duties or hospital rounds, he would need to go home briefly to gather some supplies, and he agreed to give the patient some Lasix (furosemide, a potent diuretic) in the hope that it might buy a little more time by slowing the progression of the pulmonary edema. While he was unwilling to start a TKO (to keep open) IV, he did agree to place a “heparin-loc” catheter in the median cubital vein of the patient’s right arm, and to assist her son and daughter with starting an IV after legal death was pronounced. Of note was that one of his major concerns would be the need to use less morphine for palliation than he was comfortable with, lest the patient arrest almost immediately. He said that the only reason he was willing to do this was his prior knowledge of the patient’s strong desire to be cryopreserved.

One problem that seemed insurmountable was access to heparin in sufficient quantity and concentration to serve as an anticoagulant. The other medications that I suggested be given intravenously post-pronouncement were ones that the physician kept on hand in his office: chloropromazine, Toradol (ketorlac tromethamine), Minocin (IV minocycline), five 50 ml vials of 50 mEq sodium bicarbonate and a 1-liter bag of normal saline.  Uncharacteristically, the hospital pharmacy in the small city nearby refused to dispense any injectable medications except to inpatients in their facility, despite the fact that this physician had practice privileges there.

In desperation I began searching the Internet for hemodialysis (artificial kidney) centers in the area and found one located just a few blocks from the Wal-Mart. These facilities invariably have heparin in large quantities and they also have 23% sodium chloride in 30 ml vials. That was critically important because it could be added to the liter of normal saline to create a 3% hypertonic saline solution – arguably one of the better things that could be given to improve microcirculatory flow; thus facilitating better distribution of the other medications, and possibly helping to directly  reduce ischemia-reperfusion injury. The recording on the dialysis center’s phone line indicated that they would open for business at 0500. On the chance that they might be willing to dispense heparin and hypertonic saline with a prescription from the physician, one of the family’s close friends set out again to wait until 0500.

An added advantage to this trip was that he could pick up a number of items from the Wal-Mart which we had forgotten on the first trip, including half a dozen boxes of Ziploc bags, two 2-quart plastic pitchers to scoop ice with, two 5-gallon plastic pails for adding and removing water from the makeshift PIB, and several heavy duty tarpaulins to line the air shipper cum PIB to guard against possible leaks.

Figure 3: Consumer household-type indoor/outdoor thermometer available at many discount retail outlets.

At around 0545 the registered nurse (RN) in charge of the commercial dialysis center contacted the facility’s medical director who had no objection to providing heparin and hypertonic saline on the condition that it was expressly not for medical or veterinary use (i.e., not for use on a legally alive patient). Graciously, there was no charge for these items and they were on hand at the patient’s bedside when she arrested later that day.

The patient’s son and another family member worked diligently to turn the sump pump, garden hose and lawn sprinkling parts into a working surface convection cooling device (SCCD). They then went on to attach the toilet plunger to the T-handle which had been previously fabricated from 1” plastic plumbing parts. Fortunately, the thread on the butt of the wooden dowel which had been both epoxied in place and secured with screws inside the piece of 1” PVC plastic pipe (that constituted the upright section of the T-handle), was compatible with the newly acquired rubber plunger head.

Figure 3: A simple, expedient head ice positioner (HIP) fabricated from a plastic garment storage box and a piece of foam pipe insulation. The thermoplastic typically used to manufacture these materials is notoriously liable to fracture during cutting and drilling. The cutout in the HIP pictured above was made using a (repeatedly) heated disposable box-cutting knife. A less satisfactory but easier to fabricate alternative is to use a disposable expanded polystyrene ice chest. However, in many areas these are season items, and are not available in the winter months.

A U-shaped cut out was made on one side of the EPS ice chest and this was placed at the head end of EPIB to serve as a reservoir for ice and water around the patient’s head. One of the lawn sprinkler rings was positioned between the crown of the patient’s head and the wall of the EPS cooler opposite the U-cutout. This allowed a constantly replenished reservoir of ice and stirred water to accumulate around the patient’s head providing effective cooling without splashing and spraying the water. The other sprinkler rings were distributed over the patient’s body and covered with bath towels to prevent water spraying out of the EPIB, and to more evenly distribute the ice water as a smooth sheet of cooling fluid over the patient’s body.

When cardiac arrest occurred, the physician remained on hand to assist with giving the medications and insuring that the disposable bag-valve resuscitator left by the ambulance crew at the son’s request was used correctly, since the patient was not intubated. To his credit as a human being, which also served as a testament to his competence as a physician, without any request or discussion that he do so, or that it would even be desirable, he also administered two additional doses of morphine after pronouncement during the hour and a half that cardiopulmonary support (CPS) was continued. CPS was discontinued when the AccuRite thermometer, the probe of which was placed deep in the oropharynx, registered a temperature of 17 degrees C.

Stupidity, Insanity, or Something Else?

The story above has been repeated with variations several times over the last five years, usually with a much less favorable ending. The patient in this story was lucky to have a son who understood the importance and the urgency of good care for his mother and who also had the intelligence and manual skills to make it happen. She was also fortunate to have a physician, family and friends who were willing to extend themselves so far in order to help her achieve something that most of them did not consider a priority, or even a worthwhile thing to do.

This story will mean different things to different people. Some will see it as an interesting adventure of sorts, others as a lesson in how decent and caring people can be, and still others as an exercise in technological expediency in a trying situation. All of these interpretations are valid, but alas, none of them addresses the most important issue this story raises for cryonicists, and that is how to avoid it happening again, and even more importantly, how to avoid it happening to you.

A critical reading of the various case reports published by cryonics organizations makes it clear that there are truly horrible problems that are recurring over and over again in patient transport. Patients routinely arrest before the Standby Team arrives (http://www.alcor.org/Library/html/casesummary1831.html, http://www.alcor.org/Library/html/casesummary2340.html, http://www.alcor.org/Library/html/casesummary1356.html, ), after the team has stood down (http://www.alcor.org/Library/html/casesummary1356.html) or they arrest with no help on the horizon beyond a mortician who will come, with no particular sense of urgency, and more or less pack the patient’s head in ice http://www.cryonics.org/reports/CI72.html, http://www.cryonics.org/reports/CI79.html,. Cryopatients routinely experience many minutes or even hours of ischemia not only absent cardiopulmonary support, but absent cooling of any kind. In one recent case, a patient went for 4-hours post-arrest with no ice or other refrigerant applied to her head http://www.cryonics.org/reports/CI82.html. This story is in no way remarkable, except that in this case both the patient and her spouse were committed, signed up cryonicists! How could this happen?

The answer is that it happened because of lack of information, lack of education, lack of preparation, and the complete absence of even the most basic tools to cope with an emergency that was not just a remote possibility, but an absolute certainty.  Over the years, people in medicine (outside of cryonics) who have read some of these case reports online have remarked to me, “What is the matter with these people? Are they stupid, or do they just not care?” Perhaps Benjamin Franklin comes closer to the truth with his observation that “the definition of insanity is doing the same thing over and over and expecting different results.” Are we cryonicists stupid, insane, or are we just not paying attention?

The “Big Fix”

Cryonicists tend to be focused on major technological advances and “big fixes” when they think of what is likely to be of benefit in improving the quality of their own cryonics care. There is also an understandable tendency to rely on their cryonics organization to provide the critically important instructions, supplies and hands-on care they will need in an emergency. Unfortunately, the world we live in is not one where cryonics organizations’ facilities are as commonplace as fire stations – with paramedics and ambulances no more than a phone call and three to five minutes away. In fact, as the story above illustrates, depending upon where you live, paramedics and even emergency medical technicians, may be 15 minutes or even an hour or more away. Not all cryonicists in the United States (US) live in urban areas (or even in rural areas) with good emergency services. So, if you want to improve your chances in a cryonics emergency, depending upon the breaks, it is going to be largely up to you. This will be especially true if you experience sudden or unexpected cardiac arrest.

If you live outside the contiguous 48 US states and Canada (North America), the definition of “sudden” will often be any arrest that occurs with less than 48 hours notice, or that doesn’t occur within 72 hours from when the Standby Team was deployed.

The cryonics organizations have failed miserably in providing the education, instructions, and hardware that would go a long way towards remedying this situation.  Having said this, it should also be duly noted that cryonics organizations are created and run by and for cryonicists. The contingent of the dissatisfied who rail and complain on various cryonics list serves certainly have a point, but they just as certainly are doing nothing concrete or positive to fix the problems.  Cryonics has a 40+ year history of people with big ideas they’ll talk about endlessly – and never act on, as well as people who have a never ending litany of complaints and criticisms, but nary a solution to offer or act upon. Both of these approaches result in lack of progress, and worse, demoralization and loss of credibility.

That has to change, starting now.

End of Part I

I note with bleak humor that there is actually an organization with a very slick website called the The Cryonics Society (http://www.cryonicssociety.org/mission.html) which “aims to foster support for the emerging science of cryonics by educating the public, advocating for more research, and by providing objective and unbiased information about cryonics and its benefits to everyone.” How is this to be done? Well, they advise that “to make those compassionate and humane goals a reality, human beings need to come together and to work together to achieve that end.” How? “By joining the Cryonics Society.” Sure, give us your money and we’ll tell you what you already know, namely that cryonics could save your life and lots of others. Could, that is, if it were really an attractive and practical option not encumbered with many hours of warm and cold ischemia and a generally miserable level of care.


Posted in Cryonics Technology (General), Ischemia-Reperfusion Injury | 2 Comments

The Lifebridge B2T® “Plug-and-Play” Extracorporeal Life Support System

By Mike Darwin

Figure 1: The ultra-compact, lightweight and fully self contained Lifebridge B2T® Portable Extracorporeal Life Support System.


The Medizintechnik GmbH Lifebridge B2T® extracorporeal life support system (Figure 1) is a device fast closing in on a technology I’ve long dreamed about, and even made some tentative efforts towards developing, namely, a compact, self-contained, field-able, semi-automated cardiopulmonary bypass system.1,2 It is a beautifully engineered and elegant little machine, and I believe that it represents (at least for Europe) the beginning of a transition of extracorporeal circulatory support (ECCS) from exclusive use in the operating theatre and ICU in the hands of perfusionists, to the hands of critical care and emergency medicine physicians and nurses in the Emergency Department (ED), in the Cardiac Catheterization Lab, and ultimately, in the field. It is also the latest extracorporeal technological tour de force from Germany, making that nation the world’s undisputed leader in innovative and brilliantly engineered ECCS products. As a useful aside, I would note that the first no-pump extracorporeal ventilator, the Novalung® iLA Membrane Ventilator (Figure 2) is also a product of German extracorporeal engineering.4-7

Figure 2: The Novalung® iLA GmbH Membrane Ventilator: no pump, no muss, no fuss.

When I first saw this system undergoing animal trials in Europe ~ 2 years ago, I was deeply conflicted about reviewing it anywhere that cryonics organization personnel might see my post. Historically, there has been this thirst for the “big technological fix” in cryonics, and I could see in my mind’s eye the cash changing hands in the eager hope that the Lifebridge B2T® would make bypass foolproof and easy. No such system exists, yet. Nevertheless, the Lifebridge B2T® is unquestionably a big step along the way. The device contains a PC with sufficiently sophisticated software to allow the system to pretty much prime itself! But, I’m getting ahead of myself.

System Configuration and Performance

The unit consists of three proprietary integrated units which supply every hardware and disposable component needed for emergency cardiopulmonary bypass. The entire extracorporeal circuit is contained within an injection molded polypropylene housing that snaps easily into place. The Patient Module is incredibly rugged, and it can actually tolerate being flung on the floor with considerable force without damage to the bypass circuit components inside – although this practice is clearly not recommended. [When this was demonstrated for me it reminded me of when plastic IV bags were introduced as an alternative to glass bottles. Baxter sales reps stood on them, stomped on them, and flung them off multistory buildings!]

The components embedded in the disposable “Patient Module” consist of a 400 mL hard shell venous reservoir which feeds a clone of the Biomedicus BP80 centrifugal blood pump from which blood is delivered to the oxygenator/heat exchanger and arterial filter. The Lifebridge B2T®  was originally marketed with only the  Minintech BioCor 200 Polypropylene pseudomembrane oxygenator as an option, but Medizintechnik received 510(k) clearance in December of last year to begin offering the device with the Medtronic Affinity® NT oxygenator, with either Carmeda® Bioactive Surface coating, or Trillium Biopassive Surface coating. This makes the entire system completely “heparin bonded” and “blood compatible,” permitting minimal anticoagulation. The arterial filter is a Terumo Pall AL8 40 40-micron filter with an integral bypass loop. Also molded into cassette that holds the extracorporeal circuit are disposable sensors for monitoring arterial and venous pressure (including filter back-pressure), as well as sensors air for detection, and venous reservoir level monitoring and control.3

Figure 3: The disposable, integrated Patient Module which contains the entire extracorporeal system.

There is a small, integral (also disposable!) roller pump head in the patient module that semi-automatically primes the extracorporeal circuit with lactated Ringer’s solution, and assists in ensuring the system is de-bubbled and ready to connect to the patient (Figure 5). This little positive displacement pump is also used to control volume in the venous reservoir. Fluid waste is dumped to a waste reservoir which is also contained within the patient module cartridge and is vented to atmosphere via a 0.45 micron hydrophobic filter to prevent aerosol contamination of the ambient air. The extracorporeal system is closed to air – there is no blood-air interface in the system, and this further reduces trauma to the blood (hemolysis and protein denaturation) and provides added inherent safety against air embolism.

The second element of the system is the Control Module, which houses the drive system, (the blood pump motor/controller, the drive motor for the roller pump active air elimination system, the automatic clamps for blood flow regulation, and an integrated back-up Lithium Polymer (LiPO) battery that allows standalone operation of the control and patient module. The entire system, including the transport case “suitcase” that the unit can be fielded in weighs ~20 kg. The (required) 1 liter of Ringer’s solution prime is not included in the system’s weight. Minus the carrying case, the system comes in at a weight of 18 kg (39.6 lb) – very impressive considering that the device subsumes a conventional extracorporeal membrane oxygenation (ECMO) cart and part of a perfusionist. Occluding clamps and all other instrumentation needed to safely operate the system are either integral to the device, or included within its transport case. The extracorporeal cartridge can safely remain in the system for 1-year after it is emplaced – further reducing the time from deployment to fully operational status. I was able to go from dry to primed in 6 minutes, and the manufacturer says it is easily possible to do so in 5. I believe them. The modular configuration and semi-automatic priming of the system allows for what is being termed “plug-and-play” initiation of ECC within 5 minutes.1

Figure 4: The semi-automatic priming procedure requires the pump head to be manually rotated 90 degrees so that the pump inlet is pointing up (at left, above). Once the circuit is primed, the pump and circuit are rotated in the operating position shown at left in the schematic above..Centrifugal pumps are inherently incapable of pumping macro-air because they de-prime when large amounts of air enters the pump head. The Lifebridge B2T® has cleverly built on this inherent safety feature by mounting the centrifugal pump head with its tangential outlet pointing down.1

The third component of the system is a base module with a tubular tilting frame that allows the machine to be rocked back 90 degrees to permit priming. That’s the semi-automatic part of the priming process – although the unit walks you through it a step at the time (Figure 4). The base module is surprisingly well designed and is quite stable – the locking mechanism is intuitive, and the tubular framework is rugged, so it is unlikely to become bent or distorted from being lugged around or transported in vehicles or aircraft.  The base module houses the transformer and control electronics for charging the Bullith batteries,[1] and the unit will accept either 110 or 220 VAC current. The Bullith batteries are, again, an example of where German engineering and innovation are taking the lead – they are compact, featherweight by comparison to gel cells, they hold a lot of energy for their size and weight – and nothing else on the market comes close to their reliability and performance. They also have a fantastic shelf life and do not require continuous trickle charging to keep them from spoiling, as do NiCad and NiMh cells. That means you can leave the unit on the shelf, much like an Automatic External Defibrillator (AED), until you need it – and when you do need it, the Lifebridge B2T®  can run for an incredible 2 hours without mains power.

The control unit has a conventional PC embedded in it as the “brains” of the system and the interface is a very slick touch sensitive flat panel and a rotary switch. I think the most surprising thing about Lifebridge B2T® to me was the user-friendly hardware engineering, and the intuitive Graphical User Interface that “gets everything just right.” You see the data you need when you need it, and you find the controls displayed where you want them when you want them. The rotary switch to control the pump speed is an astonishing concession to practicality and ergonomics over the “dazzling” menu driven technology which seems to be mandatory on every new consumer or medical device. When I want to turn down, or shut off a blood pump in a hurry, I do not want to be searching around on a glowing gas discharge display screen for a “virtual knob”- I want something I can instantly find, grab hold of, and twist!

Perhaps years-long exposure to US-made computer games has finally warped the GeNext German mind into sensible and understandable engineering. The Germans have always been able to manufacture beautifully crafted and engineered devices – the problem has been their often byzantine and madly complex implementations (beware of German plumbing!). The onboard PC records and stores all the typically desired case data and perfusion protocols. Patient specific data input is simple and straightforward, and there were USB ports on the machine I saw for data import/export.

Figure 5: Schematic of the Lifebridge B2T® extracorporeal circuit. All of the components enclosed boxed area on the diagram are embed in the disposable, rugged and  impact resistant disposable Patient Module.


The system was designed primarily for Cardiac Catheterization lab or Emergency Department (ED) use by non-perfusionists to serve as a perfusion and oxygenation platform for patients who present in cardiogenic shock and who need the additional “time bridge” to get coronary revascularization via angioplasty, or coronary artery bypass grafting (CABG).8,9 It will also likely find ready application in treating profound hypothermia, where it is ideal for circulatory support and core rewarming. This is a significant issue on the Continent, where skiers and other winter outdoorsmen not infrequently experience exposure.

Figure 6: At top, Members of the 59th Medical Wing Extrcorporeal Membrane Oxygenation Support Team undergoing hands-on ECMO training during an exercise on July 1, 2009, at Wilford Hall Medical Center, Lackland Air Force Base, Texas. The ECMO machine is a portable extended use cardiopulmonary bypass device that circulates and oxygenates the patient’s blood allowing time for acute lung injury or ARDS to resolve and the patient to recover. The lower picture is the current patient and ECMO hardware support cart mounted in a C-17 cargo plane. Anything that can reduce the weight and complexity of the ECMO system is invaluable under such conditions and ultra-compact and automated systems would allow for immediate application in forward, near battlefield positions.

I’ve been told that the US military has purchased Lifebridge B2T® units to evaluate in planned expanded deployment of extended (ECMO) support in cases of acute respiratory distress syndrome (ARDS) secondary to polytrauma, blunt force cardiac trauma and blast injury to the lungs (now “new” wartime pathologies as a result of body armor ‘softening the blow’ of what would have been otherwise lethal projectile impacts and much improve on site and in-field critical care medicine). The center for the military’s use of ECMO is the 59th Medical Wing at Wilford Hall at Lackland Air Force Base, TX. The ECMO capability at Wilford Hall dates back to the work of Air Force physician Gerald Klebanoff who invented the total body washout technique for treating stage IV hepatic coma in the early 1970s.10,11,12 The military commitment to this technology seems serious,13and in fact the Wilford Hall crew just had their first successful ECMO mission transporting a critically wounded soldier from Afghanistan back to Germany and then to the US for definitive treatment using a by C-17 cargo aircraft to carry the ECMO cart (Figure 6).  This operation was planned, tasked, command and controlled by the 618th Air and Space Operations Center (AOC) at Scott Air Force Base, which is the principal US and NATO agency for worldwide military airlift, air refueling and aeromedical evacuation. The military is also beginning to use Novalung technology for acute stabilization and management of patients with respiratory failure secondary to battlefield trauma.14

The primary feature that will likely expand the use of CPB and ECMO into critical care and emergency medicine is the Lifebridge B2T®’s computerized “System for Prevention of Air Embolization (SPAE).” This system employs a 7-layer deep prevention protocol using an automatic “air management procedure” that is triggered by in blood macro and micro air detection employing an ultrasonic air bubble detector placed immediately after the arterial filter in the circuit.1 If bubbles are detected, the arterial line is closed within <300 msec by means of an arterial clamp (Figure 5, #1). By simultaneously opening, the arterio-venous (A-V) shunt line, which connects the arterial line (post filter) to the venous line (Figure 5, #2), blood containing micro- or macro-air is diverted to the venous reservoir without hazard to the patient. Once bubble removal is complete, the on-board computer closes the A-V shunt and unclamps the arterial line to once again begin perfusing the patient. The seven-stage SPAE operates as follows:

1) Air entering into the venous line, or re-circulating through the purge lines, rises to the top of the venous reservoir via the buoyancy effect, where the roller pump (Figure 5) actively removes it.

2) The venous reservoir employs a two compartment design separated by a120 micron membrane, or screen. One compartment handles the venous return, and the other serves as the sump from which blood is drawn for perfusion through the oxygenator and into the patient. The devising screen effectively excludes microbubble generated as a result of turbulence, negative pressure in the venous line, or air leaks around the venous cannula, from entering the arterial intake – in effect it is a pre-arterial filter microbubble filter – a very clever and long overdue safety feature.

3) Low venous blood level is detected by a sensor that immediately stops the pump. This system is fairly “smart” in that when I regularly interrupted venous return, the machine would shut down and re-start perfusion in a dynamic fashion in response to the blood level in the reservoir.

4) An inherent safety feature of centrifugal pumps is that they will not pump macro-air. The Lifebridge B2T® has cleverly built on this feature by mounting the centrifugal pump head with its tangential outlet pointing down, making it more difficult for any air entrained in the pump head to rise under the influence of gravity and enter the arterial line.

5) As is standard on all ECCS circuits, the oxygenator also serves as bubble trap and air can be eliminated by the automatic opening of the solenoid clamp on the oxygenator recirculation line, to divert flow to the venous reservoir where it can be vented or siphoned off as required.

6) Again, as is now universal practice, the arterial filter employs centrifugal air separation using spiral flow, and this air is continually eliminated from the circuit by a bleed line atop the filter, which is in turn controlled by the PC.

7) Whenever bubbles are detected behind the arterial filter, the “air management protocol” eliminates them, as previously described. All prevention measures are inherent in the configuration of the system except for 3) and 7) above, which are implemented in the control software by the PC.

The unit has no intrinsic heater/cooler, so an additional module to perform this function must be used if ECMO support is to go on for an extended period of time, or if rapid induction of therapeutic hypothermia is desired. The oxygenators used in this platform are all rated for 6 hour use, however, as any Third World perfusionist will tell you, in most cases they can be reliably run to 12 hours; and runs of 24 hours, or longer, are not uncommon. I would also note that if the era of profound or ultraprofound asanguineous hypothermic perfusion ever arrives in medicine, the useful life of microporous membrane oxygenators will be further extended, since the membrane retains its integrity much longer in the absence of both blood and normothermia. The Lifebridge B2T® system makes switching patient modules safe, rapid and easy, so in the event the oxygenator begins to weep transudate, clots too many fibers, or otherwise deteriorates in performance, switch-out is fast.

As with other Minimal Extracorporeal Circulation (mini-ECC) systems, the Lifebridge B2T® has superior blood handling characteristics. Due to reduced tubing volume there is correspondingly less prime needed, as well as a small reduction in the total surface area of foreign material that blood is exposed to, and thus less pro-inflammatory cytokine release.[2] The hemolysis characteristics of the system in clinical use are also, as expected, quite favorable, and there seems to have been no price paid for plumbing the system into such a constrained space.1

A testimony to the trust placed in the automated components of perfusion in the  the Lifebridge B2T® is evidenced by the fact that much of the extracorporeal circuit is no longer visible to the operator. I found this very disconcerting, until I grew to trust the device’s “management” of perfusion.

The Future

I have long believed that an essential technology to a truly field-able ECC unit that can be pressed into service the instant vascular access is achieved in the field, is a pre-primed circuit incorporating a true membrane oxygenator. Such a circuit would be stored ‘wet,’ and be fully primed and ready for connection to the patient as soon as vascular access was established. With the advent of yet another German advance in extracorporeal technology, the development of the poly-4-methyl-1-pentene gas exchange membrane, now available clinically in the Jostra Rotaflow and QuadroxD true membrane hollow fiber oxygenators, this dream seems closer to a reality.15,16 However, the Lifebridge B2T® is forcing me to rethink this “requirement.” By compacting and cleverly arranging the circuit elements, priming and de-bubbling are made much simpler. There is no longer any need to beat on the arterial filter with a rubber reflex hammer, or to chase air from pillar to post in the circuit during priming. The machine is essentially self-priming. The only reason Medizintechnik didn’t make the device completely automated for priming is that it would have required the incorporation of a heavy, motorized tilt assembly to rock the circuit from the operational position to the priming position, and back again. This would clearly have been a poor engineering decision when that operation is so easily accomplished by human hands already present (and required) to operate the device. In practical terms, 5 minutes from start to patient ready, might as well be “instantaneous,” because vascular access will invariably take longer, far longer, in fact.

And that is just about the last barrier to the deployment of ECC and ECMO technology into first responder applications. There is no question that very rapid ECC would be highly effective in improving the outcome in sudden cardiac arrest if it could be applied on site, with effective CPR, such as that offered by the LUCAS device, being used only as a brief bridge in the event of failed first responder defibrillation.17,18,19 With further automation of ECC to minimize the requirement for highly developed quick reflexes in the operator, and further encoding in the machinery the complex algorithms for managing perfusion, the primary remaining barrier (aside from cost), is the inability to achieve rapid vascular access using minimally skilled personnel. This barrier seems insurmountable, but then so did the barriers to the creation of a device such as the Lifebridge B2T® as recently as a decade ago.

Figure 7: An add-on cooling module using ammonium nitrate and water, similar to the technology used in “instant ice packs” or perflurochemical evaporative cooling as used in the RhinoChill, should easily be able to emergently reduce patient brain core temperature by ~ 3oC.

One last point seems worth making and that is, regulatory considerations aside, it is easily possible to envision a very compact and disposable eutectic heat exchange module that could interface with the Lifebridge B2T® for the induction of Mild Therapeutic Hypothermia (MTH) in the field. Since only a 3oC drop in brain temperature is required acutely in MTH, the use of chilled prime solution (with another liter of chilled Ringer’s given at the start of bypass), a pre-cooled Patient Module, and the addition of a eutectic heat absorbing source, such as ammonium nitrate activated by water, or an evaporative PFC azeotrope such as is used in the RhinoChill,20,21 it should be possible to induce MTH in the field, or en route to the hospital without recourse to ice, or heavy refrigeration systems.


1)  Mehlhorn U, Brieske M, Fischer UM, Ferrari M, Brass P, Fischer JH, Zerkowski HR. LIFEBRIDGE: a portable, modular, rapidly available “plug-and-play” mechanical circulatory support system. Ann Thorac Surg. 2005 Nov;80(5):1887-92. PubMed PMID: 16242474.

2) Krane M, Mazzitelli D, Schreiber U, Garzia AM, Braun S, Voss B, Badiu CC, Brockmann G, Lange R, Bauernschmitt R. LIFEBRIDGE B2T–a new portable cardiopulmonary bypass system. ASAIO J. 2010 Jan-Feb;56(1):52-6. PubMed PMID: 20051839.

3) Maunz O, Horisberger J, von Segesser L. Bridge to life: the Lifebridge B2T extracorporeal life support system in an in vitro trial. Perfusion. 2008 Sep;23(5):279-82. PubMed PMID: 19346266.

4) Camboni D, Philipp A, Arlt M, Pfeiffer M, Hilker M, Schmid C. First experience with a paracorporeal artificial lung in humans. ASAIO J. 2009 May-Jun;55(3):304-6. PubMed PMID: 19282751.

5) Kopp R, Bensberg R, Henzler D, Niewels A, Randerath S, Rossaint R, Kuhlen R. Hemocompatibility of a miniaturized extracorporeal membrane oxygenation and a pumpless interventional lung assist in experimental lung injury. Artif Organs. 2010 Jan;34(1):13-21. Epub 2009 Oct 11. PubMed PMID: 19821813.

6) Ricci D, Boffini M, Del Sorbo L, El Qarra S, Comoglio C, Ribezzo M, Bonato R, Ranieri VM, Rinaldi M. The use of CO2 removal devices in patients awaiting lung transplantation: an initial experience. Transplant Proc. 2010 May;42(4):1255-8. PubMed PMID: 20534274.

7) Fernández P, Muñoz P, Fischer D, Méndez F, Florenzano M, Valdés S, Parada MT, Fica M, Rodríguez P, Díaz R, Rufs J. [Bridge to lung transplantation with a novel pumpless lung assist device. Report of one case]. Rev Med Chil. 2009 Oct;137(10):1363-6. Epub . Spanish. PubMed PMID: 20011945.

8) von Segesser LK, Kalejs M, Ferrari E, Bommeli S, Maunz O, Horisberger J, Tozzi P. Superior flow for bridge to life with self-expanding venous cannulas. Eur J Cardiothorac Surg. 2009 Oct;36(4):665-9. Epub 2009 Jul 16. PubMed PMID: 19615916.

9) Jung C, Schlosser M, Figulla HR, Ferrari M. Providing macro- and microcirculatory support with the Lifebridge System during high-risk PCI in cardiogenic shock. Heart Lung Circ. 2009 Aug;18(4):296-8. Epub 2008 Aug 31. PubMed PMID: 18762457.

10)  Klebanoff G, Armstrong RG, Cline RE, Powell JR, Bedingfield JR. Resuscitation of a patient in State IV hepatic coma using total body washout. J Surg Res. 1972 Oct;13(4):159-65. PubMed PMID: 5078628.

11) Cline RE, Klebanoff G, Armstrong RG, Stanford W. Extracorporal circulation in hypothermia as used for total-body washout in stage IV hepatic coma. Ann Thorac Surg. 1973 Jul;16(1):44-51. PubMed PMID: 4721190.

12) Klebanoff G, Langdon D, Wilen S, Tobias H. Total-body washout in hepatic coma. N Engl J Med. 1973 Oct 11;289(15):807. PubMed PMID: 4728761.

13) Midla GS. Extracorporeal circulatory systems and their role in military medicine: a clinical review. Mil Med. 2007 May;172(5):523-6. Review. PubMed PMID: 17521103.

14) Bein T, Osborn E, Hofmann HS, Zimmermann M, Philipp A, Schlitt HJ, Graf BM. Successful treatment of a severely injured soldier from Afghanistan with pumpless extracorporeal lung assist and neurally adjusted ventilatory support. Int J Emerg Med. 2010 Jul 13;3(3):177-9. PubMed PMID: 21031042; PubMed Central PMCID: PMC2926866.

15)  Mongero LB, Brodie D, Cunningham J, Ventetuolo C, Kim H, Sylvan E, Bacchetta MD. Extracorporeal membrane oxygenation for diffuse alveolar hemorrhage and severe hypoxemic respiratory failure from silicone embolism. Perfusion. 2010 Jul;25(4):249-52; discussion 253-4. Epub 2010 Jun 21. PubMed PMID: 20566586.

16)  Horton S, Thuys C, Bennett M, Augustin S, Rosenberg M, Brizard C. Experience with the Jostra Rotaflow and QuadroxD oxygenator for ECMO. Perfusion. 2004 Jan;19(1):17-23. PubMed PMID: 15072251.

17)  Greisen J, Golbaekdal KI, Mathiassen ON, Ravn HB. [Prolonged mechanical cardiopulmonary resuscitation]. Ugeskr Laeger. 2010 Nov 15;172(46):3191-2. Danish. PubMed PMID: 21073835.

18) Larsen AI, Hjørnevik A, Bonarjee V, Barvik S, Melberg T, Nilsen DW. Coronary blood flow and perfusion pressure during coronary angiography in patients with ongoing mechanical chest compression: a report on 6 cases. Resuscitation. 2010 Apr;81(4):493-7. PubMed PMID: 20227005.

19) Wagner H, Terkelsen CJ, Friberg H, Harnek J, Kern K, Lassen JF, Olivecrona GK.Cardiac arrest in the catheterisation laboratory: a 5-year experience of using mechanical chest compressions to facilitate PCI during prolonged resuscitation efforts. Resuscitation. 2010 Apr;81(4):383-7. Epub 2009 Dec 14. PubMed PMID: 20007005.

20) : Boller M, Lampe JW, Katz JM, Barbut D, Becker LB. Feasibility of intra-arrest

hypothermia induction: A novel nasopharyngeal approach achieves preferential brain cooling. Resuscitation. 2010 Aug;81(8):1025-30. Epub 2010 Jun 9. PubMed PMID: 20538402.

21) Busch HJ, Eichwede F, Födisch M, Taccone FS, Wöbker G, Schwab T, Hopf HB, Tonner P, Hachimi-Idrissi S, Martens P, Fritz H, Bode Ch, Vincent JL, Inderbitzen B, Barbut D, Sterz F, Janata A. Safety and feasibility of nasopharyngeal evaporative cooling in the emergency department setting in survivors of cardiac arrest. Resuscitation. 2010 Aug;81(8):943-9. Epub 2010 Jun 2. PubMed PMID:20627524.

[1] Bullith Batteries, Ismaning, Germany

[2] The primary source of blood exposure to non-native surfaces remains the oxygenator-heat exchanger and the arterial filter, both of which have enormous surface areas which are necessary for them to perform their functions.

Posted in Cryonics Technology (General), Ischemia-Reperfusion Injury, Medicine, Perfusion | 3 Comments

Don’t Ask, But Do Tell

By Mike Darwin

The wise are instructed by reason, average minds by experience, the stupid by necessity, and the brute by instinct. — Marcus Tullius Cicero

One of the things I find fascinating about so many people in cryonics is their seeming total inability to ask a direct question – or any question – of the person(s) who can answer it. One of the reasons I dislike the Cold Filter Cryonics Chat forum is the sheer stupidity of it. There are thousands upon thousands of words of more (rather than less) idle speculation about all manner of practical questions about cryonics, and yet, apparently no one ever thinks to simply ask the person or persons who knows, or might know, the answer to the questions that are under discussion.

Some weeks ago, Mathew Sullivan wrote privately to inform me that he wanted me to delete his address from my contacts list, and to never communicate with him again. Certainly, I obliged. So, in his case he has made it pretty clear that he has no interest in any answers to the questions he publicly asks about me, or my intentions (and for the record, he didn’t ask me privately, either): fair enough.

However, that still leaves everyone else who wonders (among other things),” does Mike Darwin want to:

* Turn cryonics into a secret society?

* Turn cryonics into a cult (define cult)?

* Wage war on nation states?

* Abolish capitalism?”

There is now this information-giving instrument called Chronosphere, in fact, you’re reading it. You can ask questions here, and if they are reasonable, they have a high likelihood of being answered.

What’s more, there are, conservatively so I’m told, more than a million words written by me over a period of 36 years (or more) available on the Internet. Much of it is easily and directly retrievable: old Cryonet posts, back issues of Cryonics magazine… And by simply asking, a large cache of other material can be accessed. Long before blogs were invented, a cryonicist named Brian Shock said to me, “I see why you never bothered to keep a journal – you did so in Cryonics magazine and on the Internet.” I’m certain that in all those words there’s a fair number of mistakes, and certainly many things I wish I’d said differently – with more tact and with less aggressiveness. Nevertheless, methinks it is mostly very much on point, and that there is precious little idle or uninformed speculation. But what I personally think isn’t at issue here: those words exist and, for good or ill, they stand as a record of my thoughts, and often my actions, over nearly 40 years of involvement in cryonics.

It’s a very strange situation to find people writing books about me and accusing me of murder, and all manner of foul deeds, when they have never even tried to contact me, and have carefully cherry picked a truly microscopic fraction of my public writing. But that is how it is. In his Notes From The Underground, Dostoevsky wrote: “Every man has some reminiscences which he would not tell to everyone, but only to his friends. He has others which he would not reveal even to his friends, but only to himself, and that in secret. But finally there are still others which a man is even afraid to tell himself, and every decent man has a considerable number of such things stored away. That is, one can even say that the more decent he is, the greater the number of such things in his mind.”

Perhaps my fault has been in being indecent, or being incapable of keeping such thoughts stored away? In either event, what I have written over a lifetime is, I think, by any measure surprisingly candid and unguarded.  While my personal psychobiology is probably the major reason for this candor, another was my experience when I first became involved in cryonics.

I got interested in cryonics when I was 13 years old. By the time I was 14 I had real doubts and concerns about the veracity of what I was being told about various cryonics operations. I heard terrible rumors about the people then in positions of authority in cryonics. My response was to write countless letters asking questions, mow lawns to make money to pay for long distance phone calls, and finally, to GO AND SEE FOR MYSELF. I’ve attached a record of two of those “journeys made in search of the truth” when I was 15-17 years old – posted on Cold Filter, no less (and to no good result, as far as I can tell).

When these things happened I was a child (and if you doubt it, just look at the picture in the press clipping here), and I lived in a time when long distance phone calls were an exotic thing that cost a fortune. Even though I made money to pay my long distance bills, that didn’t stop my father from beating the crap out of me when a $40 bill came in the mail, one winter’s day. He was simply outraged that anyone, let alone his own son, would spend that kind of money (in 1968!) on phone calls. After that, I used the pay phone at Teeter’s drug store on the corner, and fed quarters into it as the calls went along.

We now live in an age of bundled long distance and Skype – I can chat, and see the person I’m chatting with in London, or Moscow, or Jakarta – for nothing more than the cost of the DSL hookup. I can mail people for free – no arduous pecking with one finger at the typewriter, buying the stamp, putting it in the mail… And so can you! Communication has never been easier!

And if you don’t like the answers you get, or more correctly, if you don’t trust them – then it has never been easier to GO AND SEE FOR YOURSELF.

So, I just don’t get it. And I find it impossible to have respect for people who treat cryonics in this way. When I was still a child I already realized that cryonics was important to my survival. In fact, I realized that it was absolutely essential to my survival, and to my temporal well being and happiness. Very soon afterwards, I realized that I loved cryonics – loved it as a parent loves a child, and as a child loves a parent. Cryonics gives hope, sanctuary, and the prospect of an indefinitely long life of inquiry, growth and joy; and it demands in return respect, hard work, and genuine care and concern for its well being and its survival.

So, I’ll be perilously frank, yet again. When I look at the countless bytes and the countless hours (over many years ) of time spent by people on the Internet nattering away about mostly imaginary problems in cryonics (the real ones are much, much worse), I have to work really hard not to feel disgust. Yes, they have the perfect right to spend their time, talents and money in this way (although I am disheartened to see that they are not often held accountable for veracity of their statements, their predictions, or their speculations). But the waste is heartbreaking.

This may seem weirdly tangential, but I strongly suspect that most of the people who engage in this behavior have no savings, and don’t save money. I say this because the expenditure of so many small increments of thought and labor, over such a sustained period of time, is the intellectual and moral equivalent of being a spendthrift. There is, inherent in such behavior, a lack of appreciation for the fantastic (and compounded) value of putting a little effort towards a project, over a long period of time, to a good end. So, I would say to such people (as I have said before, privately), print out your diaries, or gather them into one ‘virtual spot’ and read them. Read everything you have ever written about cryonics, if you can – or at least everything you can retrieve. Diaries are always embarrassing, because they show us how little we really knew about the world we inhabited when we wrote them (and thus imply how little we almost certainly know about the world we inhabit now), and especially because they tell us what truly terrible prophets we are. No elegant words will do here: we suck at predicting our futures, let alone anyone else’s. So please, before you read my life’s diary, take a few hours and read your own. I promise you that the exercise will be well worth your while.

Meanwhile, I am reposting my original missive to Cold Filter, here. The photo links long ago expired, and I have made minor grammar and punctuation corrections, although probably not nearly enough. The URL for the original post is included, in case there are any questions. This is the story of one of my many journeys of discovery in cryonics. If you set foot to path, you can have many of your own – if you have the courage for them.

SETTING THE RECORD STRAIGHT ON BOB NELSON: A Cold Filter Dialogue between Mike Darwin & Ken Bly

Response to Cryoken (corrected)

June 19 2007 at 7:35 AM

Original text is at: http://www.network54.com/Forum/291677/message/1182252950/Response+to+Cryoken+%28corrected%29

KEN WRITES: Mike Darwin has in the past, accused Bob Nelson of undercutting the prices of the Cryonics Society of New York (CSNY, as wells as bad-mouthing the sister organization, in order to lure away their patients. These accusations have severely damaged Bob Nelson’s reputation, and they are not true.

MD’S RESPONSE: I have stated what I reasonably believed then, and reasonably believe now, to be facts based on personal experience. In many cases these experiences were the same ones other people had at the time, and where I know this to be the case, I will give their names and the approximate dates. A few of these people are still living and compos mente, unfortunately, most are not.

Before I proceed further, it is important that I communicate both a time-line and what will be the first of a great deal of context. First, the time-line: I was born in April of 1955 and am currently 52-years-of-age. This is of significance because it means that on 12 January, 1967 when James H. Bedford was cryopreserved, I was not yet 13-years-old. I became aware of cryonics sometime in January 1968 when I was presenting my Science Fair project entitled, “Suspended Animation in Plants and Animals,” at the Regional Indianapolis, IN Science Fair, held at Butler University Field House. In response to my disbelief that humans were being “frozen for future revival,” I was handed a copy of this article, from either the Indianapolis News or the Indianapolis Star (at that time, and for sometime afterwards, I did not understand the importance of noting the source and date of clippings or articles):

This article provided no viable contact information, and it was not until a few weeks or months later that my father brought me another article on cryonics which had appeared in Men’s True Life magazine. This article mentioned Cryo-Care Equipment Corporation in Phoenix, AZ and its President, E. Francis (Ed) Hope. Using directory assistance, I was able to get the address of Cryo-Care, and I wrote a letter to Mr. Hope asking for information. Mr. Hope wrote me back with the contact information for four cryonics organizations: the Cryonics Society of California (CSC), the Cryonics Society of New York (CSNY), the Cryonics Society of Michigan (CSM), and the Life Extension Society (LES). I wrote to all four organizations and received a response from three: CSNY, CSM, and LES. I received a large package of information from CSNY, a tri-fold (single page) brochure from CSM, and a few back-issues of FREEZE-WAIT-REANIMATE, the LES newsletter from LES. In addition to the package of material from CSNY, there was a personal letter from CSNY Secretary Sail Kent. Subsequently, I subscribed to CSNY’s monthly magazine, CRYONICS REPORTS, CSM’s monthly newsletter THE OUTLOOK, and LES’ FREEZE-WAIT-REANIMATE (which shortly thereafter ceased publication).

I rapidly became deeply involved in cryonics, facilitated in no small measure by a personal correspondence between Saul Kent and I. Saul almost immediately put me in touch with a student at Estancia High School in Costa Mesa, CA, Greg Fahy. Greg had founded the Cryonics Youth Association (CYA) and he provided me with back issues of the CYA newsletter, CRYONICS NEWS. Greg and I also began a fairly intense correspondence at this time. From Greg, I obtained information on how to subscribe to CSC’s newsletter, CRYONICS REVIEW. The CSC newsletter could only be had by joining CSC as an associate member, which cost $25/yr, a very large sum in those days. I mowed laws for spending money and it took quite a few lawns to come up with the $25.00 to join CSC. I sent in my money to CSC around the end of July in 1968 and never got a response (or my money back) from CSC. However, Greg Fahy was kind enough to provide me with copies of CRYONICS REVIEW, since he had access to extra copies via his friend Bob Nelson.

During 1969-1970 I began correspondence and phone contact with cryonics activists across the US, and with the Soviet cryobiologist Vladimir Negovski (correspondence only). Long distance phone calls were extremely costly at that time, and perhaps even more to the point, were considered an extravagance reserved for emergencies, or at least substantive business matters. Nevertheless, I soon learned that the only way to get a really broad bandwidth of information was to talk with people on the phone, and as a consequence, I began working at odd jobs and mowing more lawns to get money to pay for long distance phone calls. This was a source of genuine conflict with my parents, who considered such phone calls wasteful and financially irresponsible. So bad was the friction from this that I sometimes had to use payphones, which were even more costly, and required endless amounts of change.

Additional important context is that my parents were middle class people, arguably working class people, whose values and financial means were hardly cosmopolitan. My father was an Indianapolis police officer, and my mother supervised data entry (key punch operations) at Dow Chemical-Pittman Moore’s operations in Indianapolis. We lived with my maternal grandfather in his house, and while we were certainly not poor, luxuries consisted mostly of more and better quality of the basics in life. Dining out was rare, and our first television was purchased in the run-up to the Cuban missile crisis in 1961. My parents were (and are) profoundly conservative and deeply religious people whose morality and world-view was shaped by the pre-Vatican II Catholic Church. While obviously in many ways very different, I was also at the same time in many ways a product of my home life and upbringing. I was not sophisticated in the ways of the world, and I was not well equipped to separate truth from falsehood in a complex and novel discipline such as cryonics, and neither were my parents.

These phone calls were invaluable because they allowed me to talk at length with Curtis Henderson (President of CSNY and Cryo-Span) and others who had some technical knowledge of cryonics, which was essential, because I had decided to create an emergency response, cryoprotective perfusion, and temporary dry ice storage facility in Indianapolis. I thus had many practical and technical questions which could not be addressed well by mail. During the winter of 1970 I began construction of a dry ice storage box, and began purchasing the equipment, chemicals, and other supplies required to carry out cryoprotective perfusion. By 1970, at the age of 15, I had (although I didn’t know it at the time) the most sophisticated cryonics rescue and perfusion facilities anywhere in the world.

By late 1970 I had acquired enough Ringer’s solution and dimethyl sulfoxide (DMSO) to prepare over 50 liters of cryoprotective perfusate (20% DMSO). The 12 boxes in the top photograph below (with the “Cutter” label on them) each contain 6 liters of lactated Ringer’s solution, and the Fischer Scientific boxes (with “F” on the label) each contained 1.5 liters of DMSO. In 1970, 50 liters of cryoprotective perfusate was considered an extravagant amount. The balance of 22 liters of Ringer’s was to be used for blood washout prior to cryoprotective perfusion. Also visible on the metal cart at the right of the picture is a coil-type stainless steel heat exchanger that I had had custom made by an engineer at Eli Lilly & Company, who also did free-lance work:

By working at the Indianapolis Convention and Exposition Center I had made enough money to purchase the Cryo-Span Amtec model 209 industrial roller pump, and had paid a local glass blower (who also worked for Eli Lilly) to reduplicate the CSNY glass bubble trap and arterial pressure monitor:

The quality of the photos above is very poor; they are Polaroid’s from 1970. The original CSNY bubble trap can be better seen in the image below:

The Cryo-Span Amtec 209 roller pump (for perfusion) is in the foreground of the picture below. It is painted green – the pump head is metallic silver (to the left of the motor & controller assembly):

I had also constructed a dry ice box for freezing and temporary storage of cryopatients by the end of 1970, and I am pictured with this box (in the shed in back of my home in the summer of 1971) shortly after it was stained and the interior foam covered with painted plywood (see below):

Also, sometime in 1971 I had purchased the Cryo-Span Westinghouse Iron Heart (forerunner to the Michigan Instruments Thumper CPR machine) for $400. This photo shows it sitting atop the bureau in my bedroom on Lincoln Street, in Indianapolis:

By 1971 the CYA had renamed itself the Student Cryonics Association (Greg Fahy had gone onto college and felt the word “student” was both more dignified and descriptive). An SCA group had formed in Indianapolis, and in June of 1971 the SCAI newsletter documented the progress made in cryonics readiness in Indianapolis to that time (below).

It was during this time (1969 – 1970) that I began to hear statements attributed to Bob Nelson of CSC that CSNY was not storing its patients properly, that CSNY Officers Saul Kent and Curtis Henderson were over-charging CSNY patients, and that CSC offered superior care at a much lower cost. I initially heard these statements from Lucile Doty, who was then President of the Cryonics Society if Illinois. Soon thereafter, I heard the same statements, again attributed to Bob Nelson, from Loren Fitzgerald in San Diego, CA and Jack Nixon in Akron, OH – both “Cryonics Coordinators” at that time. I became very concerned that maybe I had joined the “wrong” cryonics society, and during a my Freshman (High School) 1970 Christmas break vacation I went with my girlfriend and fellow cryonics activist at the time (Ella Vinci) to visit with Lucille Doty in Chicago, IL. It was while visiting with Lucille that I finally managed to reach Bob Nelson by phone and talk with him personally about these issues. This was not easy to do because Nelson could be reached only via the CSC answering service. He would then (infrequently as I later learned) return the call. In my experience (I sent more than a dozen letters) Nelson never answered written mail. I had tried calling Nelson from my home in Indianapolis and leaving my name and number, but had never gotten a call back. This time, with Lucille Doty making the call, the call was returned the next day.

A photo of me with Lucille Doty in her Chicago apartment in January of 1970:

I asked Nelson about CSNY and he told me (this from notes made at the time) that their (CSNY’s) operation was “very substandard” and that “they are not storing the bodies properly. Henderson charges the family a fortune for liquid nitrogen, but he only keeps the capsules about 1/3rd full. That’s like medical malpractice because any cryobiologist will tell you that you have to keep tissue specimens completely covered in liquid nitrogen. I’ve explained this to Nick DeBlasio, and put him touch with our scientists at CSC, and I think he is going to move his wife (Ann) out of the Cryo-Span facility in the near future…CSNY is operating illegally and they do not have a secure underground facility which is immune to radiation in the event of nuclear attack, such as the Cryonic Interment facility will be here in Southern California…While he is far too much of gentleman to say so, Bob Ettinger’s, actions speak louder than words, and Bob always refers patients for suspension to CSC, not CSNY. I think the fact that the father of the movement refers patients to us should be all you need to know…It is widely known that Curtis Henderson has a serious drinking problem and that may be one reason that the storage at Cryo-Span is not what it should be…We charge less than a quarter of what Cryo-Span and CSNY charge a year for storage. We can do that because we have a lot more patients and because liquid nitrogen is cheaper here in California. In fact, sometimes I get liquid nitrogen for free because we get it by “bulk delivery” in a large tank-truck and I know the driver. If he has have LN2 still in the bulk tank at the end of his delivery route, then he will often just empty out the tank and we don’t have to pay for the extra nitrogen.”

I confronted Curtis Henderson with these charges via telephone, and even though it has been almost 40 years ago, his response is still clear in my mind (sic):

“What do you want me to tell you? I could spend hours arguing against Bob Nelson’s lies, but it wouldn’t do a bit of good. If you really want to know what is going on out here (i.e., CSNY & Cryo-Span) then you need to come out here and see for yourself. And, the same is true for CSC and Cryonic Interment. That’s the only way. You have to go, and you have to see for yourself, and you have to make up your own mind, because otherwise it’s just a bunch of charges and counter charges. Even when you get into a court of law where there are supposedly some standards of evidence, it is very difficult to find the truth unless you have unrestricted access to the facts. Now, you are very fortunate to be asking these questions now because we (CSNY & Cryo-Span) and Nelson (CSC & Cryonics Interment) are right here, and if you really want to know, all you have to do is come and see for yourself. So, that’s all I really have to say; come and see for yourself.”

I wasn’t very happy with this response and decided to call Curtis’ bluff and ask him when I could come, and if I could stay with someone at CSNY. Perhaps because I was only 14-years-old, Curtis Henderson told me I could come anytime I liked, and that I could stay with him and his (second) wife and two kids on Long Island, at his home (which was also where the CSNY office was located). Maybe he thought that it was exceedingly unlikely that a teenage kid would show up on his doorstep? If so, he was mistaken, because a few months later I was at 9 Homes Court on Sayville, Long Island, doing exactly what he said I should: seeing things for myself. This was the first of two summers I would spend at CSNY sleeping on the day bed in the CSNY office with unrestricted access to CSNY and Cryo-Span files and operations. The third summer I spent at CSNY/Cryo-Span was at the Cryo-Span facility on Long Island.

So, I am in a very good position to comment on the statements you make below.

KEN WRITES: “The CSNY was experiencing their own financial woes. They had underestimated the costs associated with maintaining the leaky Cryo-care capsules (sound familiar?), and as a result, the mortuary where Steven Mandel and Ann DeBlasio were stored, had threatened to lock the doors and refuse liquid nitrogen deliveries until either the past due rent was paid, or the patients were significantly decomposed. Pauline Mandel and Nick DeBlasio received letters from the mortuary with this threat (I have the letter to Mandel). Out of desperation, Pauling Mandel contacted Bob Ettinger. Ettinger recommended she go to Bob Nelson.”

MD’S RESPONSE: First of all, the CSNY patients were not initially stored at a mortuary, but rather at Washington Memorial Park Cemetery in Coram, Long Island. The “facility” consisted of a room that could not be locked and which was used by cemetery maintenance personnel (who not infrequently left cigarette butts and empty paper coffee cups on the floor, and around on the dewar platforms). Secondly, there was only one Cryo-Care dewar (Steven Mandel’s) and the vacuum was continuously maintained by a vacuum pump. While it is technically correct to refer to the Cryo-Care (CC) dewars as “leaky” in that they required frequent hardening of the vacuum with a mechanical pump, it is only fair to point out that they were not designed to have a “permanent” vacuum – the header on the patient insertion end of the dewar outer can was sealed (and held in place) with a silicone-greased O-ring. It would be equally fair (or unfair) to describe all of the patient cryostats in use by the Cryonics Institute today as “leaky,” because they too require frequent hardening of the (soft) vacuum that is used (with perlite) to insulate them. Providing a vacuum pump was used to keep the vacuum hard (which it was at CSNY) the Cryo-Care dewars actually performed very well, even by today’s standards, boiling off about 5.5 liters a day, which was what their design specifications called for.

Nevertheless, nobody (and especially not Curtis Henderson) was satisfied with the CC dewars – not primarily because of boil-off, but because of the difficulty attendant to sealing the units in the field (the inner can had to be welded shut under cold conditions), the fact that they were dependent upon electricity because they required an electrically operated vacuum pump, and that they consumed an inordinate amount of floor space. For these reasons, Curtis Henderson, working with Minnesota Valley Engineering (MVE), came up with a “stretched” version of the MVE A-9000 dewar. The A-9000 was a waist high dewar used primarily for storage of cattle semen and tissue culture cells. With the sole exception of Steven Mandell, all the other CSNY patients (Ann DeBlasio, Paul M. Hurst, Sr., and Herman Greenberg) were stored in MVE dewars which were very economical (4.5 to 5.5. liters per day per patient) and incredibly reliable. In fact, the upright MVE dewar in the picture below was later sold Trans Time, Inc., and to the best of my knowledge still has a good vacuum 39-years later. This is a photo taken in 1969 of the Cryo-Span storage facility in Washington Memorial Park. Ann Deblasio’s dewar is the upright MVE unit near the back of the picture. Barely visible on the platform in front of it are family pictures:

Your statement “(CSNY) underestimated the costs associated with maintaining the leaky Cryo-care capsules (sound familiar?)” is incorrect. The estimates for the cost of cryopreservation presented to the public ranged from $8,500 posited by Bob Ettinger in THE PROSPECT OF IMMORTALITY in 1964 to the $10,000 widely quoted by the media as being the cost of indefinite cryopreservation at both CSC and CSNY during the period from1969 to 1972. Of that $10,000 no less than $8,000 was to be invested for long-term care. $8,000.00 in 1969 had about the same buying power as $44,561.80 in 2006, or roughly twice what CI currently budgets for long-term storage for Option One Members (~$23,000 per patient). The problem was that this money was never set aside, and indeed never existed in the first place. What’s more, with the exception of Paul Hurst, Sr. (and later Herman Greenberg), CSNY was not consistently paid, or in the case of Steven Mandell, paid at all. Steven’s life insurance was applied for after he was already (terminally) ill and did not pay out. Pauline Mandell never paid Cryo-Span for the CC dewar, the charges for “encapsulating” Steven, or for liquid nitrogen or facility floor space (rent). The $4,500 for the CC dewar, the ~ $1,100 for the Sergeant-Welch vacuum pumps, and the costs of welding, transportation, and miscellaneous hardware were paid for by Curtis Henderson.

I’ve no doubt you have a letter from Washington Memorial Park threatening eviction. I only knew him by his last name, Campbell, but by 1970 Washington Memorial Park’s manager wanted Cryo-Span out of there – and it had nothing to do with nonpayment of rent. Rather, the cemetery had come to realize that cryonics was not going to be a viable business venue for them, and worse still, they were under intense pressure from their colleagues and the cemetery board to dissociate them from cryonics. Making matters worse still was the fact that the Suffolk County Health Department refused to issue burial (disposition) permits for the patients stored in the Coram facility. Cryo-Span was asked to leave. What you have also not said here is that because of the objections of Nick DeBlasio and Pauline Mandell (the two were romantically involved at the time) Cryo-Span could not get their permission to move Steven and Ann to a leased facility in a nearby industrial park. DeBlasio and Mandell insisted that the only legal venue for storage of cryopatients was a cemetery. Unfortunately (or rather very fortunately, as things turned out) Curtis Henderson had decided that he was through dealing with cemeteries, and that cemeteries were not a workable place to store cryopatients. So, the impasse continued, and Mr. Campbell grew both angry and desperate. On the occasions when I saw Campbell and Henderson interact it was not over unpaid rent, but rather because the patients were not being moved, and that the cemetery was “washing its hands of frozen bodies.”

KEN WRITES: Bob Nelson went to New York and was able to get the mortuary more to give the NYCS and Mandel and DeBlasio to come up with the money. Mandel set up a meeting with Bob to arrange a meeting with her, DeBlasio, and Bob. They both desperately wanted out of the NYCS. Mandel arranged to have Steven Mandel shipped to the CSC, ad ultimately to the vault in Chattsworth. She agreed to make monthly payments for storage and maintenance (which she defaulted on, by the way). DeBlasio, on the other hand, demanded to have full control over his wife’s suspension. Bob suggested DeBlasio build himself a vault similar to what Bob had built in Chatsworth. Bob suggested that Mandel and DeBlasio share the vault, but neither wanted anything to do with that. Bob, funded and arranged the building of the vault. DeBlasio eventually paid Bob back. Bob never had control over the day-to-day operation of DeBlasio’s vault. DeBlasio wanted out of the NYCS and wanted full control over Ann’s suspension.

MD’s RESPONSE: From first-hand observation I can tell you that the decision to move out of Washington Memorial Park by Cryo-Span was only delayed by Mandel and DeBlasio. Cryo-Span rented an industrial bay in Farmingdale, L.I., NY and sublet half of it until they could occupy it. The delay was due to Nelson’s (repeated) missed dates for removing Steven Mandell to Chatsworth, and later Ann Deblasio to Mt. Holiness Cemetery. Ann was the last to be moved, and that took place on 17 September, 1971. Shortly thereafter, Paul Hurst, Sr., the only other CSNY patient, was moved to the Cryo-Span facility in Farmingdale.

I spent a good part of the summer of 1971 at CSNY/Cryo-Span and below are pictures of the Farmingdale facility. This is a photo of the exterior of the Cryo-Span facility in Farmingdale. The small green car is Curtis Henderson’s. Barely visible in the window (above the blue van) is the Cryo-Span logo designed by Vaugh Bode, which was adjacent to the company name:

Photos of me at the Cryo-Span facility during dewar filling in August of 1971:

The Cryo-Span facility was small and unpretentious; however the patients were well cared for. Context is critically important because, you see, with the exception of Nelson telling me that Curtis Henderson and Saul Kent were dishonest and price gouging, just about everything else he told me about Cryo-Span was “true.” Patient dewars were kept between ½ and 1/3rd full of LN2 because the relatives refused to pay more, and because a different set of cryobiologists had advised them, correctly as it turns out, that most biological specimens are stored in LN2 vapor, not submerged in LN2. As it turns out (aswe have learned over 30 years later), the real issue is not so much the temperature out of the LN2 in the dewar (which Greg Fahy and I measured at ~ -150 degrees C at the patient’s head in a dewar 1/3rd full of LN2), but rather thermal cycling between -196 degrees C and -150 degrees C, which causes much additional fracturing. Once the patient is completely solidified below the glass transition point (Tg) of the tissue and cryoprotective(s), chemical change is halted, regardless of what is predicted on the basis of the Ahrrenius equation. Ironically, the Cryo-care dewars with their horizontal configuration (and the patient being stored in the upper half of the cylinder) had to be allowed to boil off sufficient nitrogen to expose the patient to vapor in order to allow room for refilling with two 160 liter (LS-160) fill dewars. This is photo of a Cryo-Care dewar with the stretcher (and thus the patient) occupying the upper half the LN2 reservoir in the inner can:

If bulk delivery was used to refill a CC dewar on a monthly basis then the dewar had to be allowed to run down to 1/3rd to 1/4th of LN2 capacity; meaning that the patient spent at least half of the time at ~ -150 degrees C and the other half at -196 degrees C, with the transition between LN2 and vapor temperature being achieved by quench cooling in LN2! The important point here is that Curtis never lied, and he never told anyone he was offering immersion storage in LN2. In fact, that service was not offered by any cryonics service provider until Trans Time started offering storage in 1973. Even then, it was almost impossible to fill the dewars often enough to avoid exposure of at least the sleeping bags the patient’s were wrapped in, since the distance between the patient and the bottom of the dewar necktube, was typically less than 10 inches. The photo below is of the inside of a patient dewar at Trans Time in 1981, and shows the close proximity of the patient’s feet to the necktube of the dewar (the bottom of which is the highest level to which LN2 can be added):

The solution to the problem was to do what Curtis Henderson had wanted to do from the start, namely to put the patient’s into the vertical MVE dewars head down with their feet closest to the neck-tube. Ironically, it was the families of the CSNY patients, in particular Nick DeBlasio, who refused to allow this, and who considered it, “disrespectful and cheap to stand patients on their heads.”

It was also true that Curtis was an alcoholic. However, what was not said was that despite his drinking problem, he worked 12 to 14 hours a day, 6 and often 7-days-a-week, on the swing and night shifts at Sonic Records, on Long Island. He did this because he had to be free during the business day to go and pick up LN2: welding supply firms are only open from 9 to 5 for LN2 pickup, and not at all on weekends. He also had to pay the lion’s share of the bills to be keep patients cryopreserved. Sonic was something out of Dante’s inferno, a terrible place to work which was hot, dangerous, and noisy. Safety and worker protection were non-existent, and the acrid stench of molten vinyl chloride, coming from open vats well over 12 feet high (with unprotected catwalks), was dizzying. I vividly remember Curtis coming home with a broken arm in an air-splint, picking me up to help him, going for LN2, filling the dewars, and only then going to the emergency department to have his arm X-rayed, properly set, and casted. The absolutely critical (but missing) context was that Curtis Henderson (and CSNY and Cryo-Span) were honest, and despite terrible personal hardship and inconvenience, they did keep their patients cryopreserved, and they did not lie about what they could offer, nor did they denigrate CSC and Cryonic Interment.

I look back on Nelson’s remarks to me in 1970 (and later) with bitter contempt. Protection against radioactive fallout? Immersion storage of patients at a 1/3rd the cost of Cryo-Span? He lied to a 15-year-old kid who was just trying to find his way in cryonics. He lied, and he lied in a way that was malicious and damaging to others, and that caused me to question the integrity of a man who had told me only the truth, however unpleasant and inconvenient that was for both him and me.

KEN WRITES: Mike accuses Bob of luring the NYCS’s away. Nonsense. DeBlasio and Mandel had good reason to seek out Bob. Their loved ones were about to have their suspensions by the mortuary where they were stored.

MD’S RESPONSE: While I believe that Bob’s claims of better service at a lower cost were certainly material in the decision Pauline Mandell and Nick DeBlasio made in pursuing service with CSC and Cryonic Interment, I have never said that this was the main reason they moved Steven and Ann, or that they were “lured away.” Nick DeBlasio and Pauline Mandell were both angry and frustrated about cryonics in general, and CSNY and Cryo-Span in particular, long before Nelson slithered into the picture. Both wanted cryonics to be something it would not become for at least another 20 years: clean, clinical, professional in appearance, and above all affordable. In Pauline’s case affordable meant “free,” and in Nick’s case, it meant whatever he thought it should cost based on standards he set and changed arbitrarily. Nick complained bitterly about the cigarette butts on the floor at Washington Memorial Park (BTW, neither Curtis nor Saul smoked, or ever has), about Curtis’ “lack of professionalism” and about Ann not being kept covered with LN2. So, as you point out, he moved Ann to the Cryonic Interment East Coast Facility (see below) and began caring for her himself and eventually another CSC patient from the West Coast, as well. What were his standards? How did he do? Well, on 27 July of 1980 I got see just what Nick DeBlasio AND Bob Nelson did with Ann DeBlasio and the other CSC patient stored with her.

I found Ann’s dewar sitting a black hole in the ground with no electric power having ever been run to the vault (and thus no lighting or alarms) sitting in ~6 inches of foul water. The wood-paneled walls of the “facility:” were almost completely covered with white mold or mildew. The once pristine white dewar looked like this as it was hoisted out of the facility:

The lid of the dewar which covered the neck-tube had been retrofitted with bulk delivery pipes. The lid was denuded of paint from the repeated overflow of LN2 and was dented and distorted from being struck with objects to free it of ice which accumulated on it due to the heat leak from the bulk fill pipes (which were un-insulated) and the high humidity from the half a foot or more of standing water on the floor:

Incredibly, the photo below shows the base of the dewar – the support bottom header and the legs upon which it rested are covered in rust. This incredible because the entire dewar was made of 312 stainless steel!

In 1969-70 Nick DeBlasio and Pauline Mandel were given free space by CSNY to run this ad in CRYONICS REPORTS:

This is Ann DeBlasio, the ad proclaimed, and indeed, this was DeBlasio when CSNY was caring for her, and it is Ann DeBlasio as I first saw her, and as I like to try and remember her:

It was my unhappy task, (and that of fellow cryonicist Joe Allen) to remove Ann DeBlasio, or more properly what was left of her, from that dewar, as well the badly decomposed remains of another woman, the CSC patient whom Nelson and DeBlasio had placed in the dewar with Ann. You are fortunate that I cannot convey the horrible odor which accompanied the image shown below:


It took us nearly a day of uninterrupted work to free those two women from that dewar. A major reason for subjecting myself and Joe to that horror was to protect cryonics from what could have been, and in my opinion would have been, another scandal of Chatsworth proportions – coming right on heels of Chatsworth itself. The stench from the decomposing bodies was wafting over to the nearby homes (one of which you can see in the background) and the cemetery management was nearly hysterical and on the verge of calling the health department. Another reason was to give some closure to the son of the other woman in the dewar. He was decent, sincere, and wealthy professional who had considered CSNY, but had gone with Nelson instead because, as he told me at the time, of Bob’s claims of superior service, underground storage, and more competitive price. This patient died not on the East Coast or in the Midwest, but rather in Beverly Hills, CA on 13 November 1972 and was sent cross-country by Nelson to be stored in Cryonic Interment’s East Coast facility! Here was a man who truly was “lured away” from CSNY. And he was not the only one who was affected by Nelson’s lies. In December of 1972 CSNY cryopreserved another patient. This woman was the first patient I cryopreserved, and her wellbeing and continued survival were incredibly important to me. The photo below was taken of me with this patient about 2 days after the start of her cryopreservation (I was 17-years-old at the time):

Solely on the basis of Nelson’s assertion that he could store this patient for less money, and more securely underground in a “permanent” facility, her family decided to have her transferred to Nelson’s East Coast Facility in Butler, New Jersey. The MVE dewar which had been on order for her was, upon completion, shipped to Mt. Holiness in Butler, where it sat, still crated at the side of the road, near the Cryonic Interment East Coast Facility for many months. The patient’s relatives (truthfully, I believe) testified that Nelson took their money (around $2,000, if I recall correctly) and never showed up to “encapsulate” their mother. This family then made the decision to bury their mother, something they had wanted to do from the start, but which Nelson gave them an excellent excuse to follow through on. Sadly, this patient had provided ~$30,000 for her long term care, but to no avail.

A year later, when Cryo-Span had closed it doors after Gillian Cumming’s death, another patient I cryopreserved avoided ending up at Mt. Holiness only because I repeatedly and emphatically warned the next-of-kin (the patient’s wife and son, respectively) against Nelson, CSC and Cryonic Interment. It took considerable effort on my part to persuade this family to send the patient to Trans Time which, at that time, was operating out of Art Quaife’s home and did not have a single patient, let alone a storage facility. It took even more effort to persuade a very burned-out Curtis Henderson to fly to the Bay Area and assist Trans Time in setting up storage operations. The patient’s relatives had to spend many thousands of dollars for capital equipment, leasing a building, and paying storage fees many times more than that for which Bob Nelson told them he could do the job, and do it better. The dewar this patient went into was the one that had been sitting at Mt. Holiness for the better part of year: the relatives sold it in a cash transaction* in the cemetery in the dead of winter* (half of the proceeds were collected by Curtis Henderson on the spot to pay the unpaid dry ice storage bills owed to him and which had paid for out of his own pocket). A few years later this patient’s wife joined him in cryopreservation (she was Jerry Leaf’s second patient and Trans Time’s third). Today, both of those patients are still cryopreserved and in fact, the husband is the second longest surviving patient in storage. The only other patient to survive prior to 1973 is James Beford, whose son had the good sense to remove him from Nelson’s care almost immediately after he was frozen in 1967.

I could be so emphatic About Nelson and CSC because in the early summer of 1971 I had gone with Greg Fahy on the Super Chief (transcontinental train) to Los Angeles and tried to visit CSC, see the Cryonic Interment facility, and meet with Nelson. I was not allowed to see the CSC facility, but I did get to meet with Nelson who told us that Joe Klockegether had all the CSC perfusion supplies and equipment at his mortuary in Buena Park, CA. Greg and I then went to the Klockgether-Renaker Mortuary, and all Joe Klockgether was able to show us was an embalming room with embalming equipment. I photographed that visit and here are the (representative) results:

The outside of the Klockgerther-Renaker mortuary:

Mike Darwin (left), Greg Fahy and Joe Knlockegether.

This it, this is all the “highly specialized equipment” assembled by CSC’s scientists to do human cryonic suspensions:

Joe, clearly embarrassed, wandered around the funeral home looking for, “a bottle of DMSO which I think we have somewhere here.” He gave up when it wasn’t in the closet where the chicken soup powder was kept for the hot soup machine. Here I was, 16-years-old, and I had vastly better equipment and chemicals (including mortuary tools and cannula) in my bedroom, and in the shed behind my house! There was nothing there in the way of cryonics equipment or chemicals at the Renaker-Klockgether mortuary, not even a dry ice box! Nelson had sat in the coffee shop where he met us and lied to us, lied to us in the expectation that a couple of “kids” were not going to exercise due diligence and check out every claim he made. And, why should he have done otherwise? Every adult, every journalist, every concerned relative, and every CSC member (with the exception of Fred and Linda Chamberlain) believed every lie he told them, and they never bothered to go and see for themselves what the truth was.

And, while I did not get to see the CSC facility, I did track down the welder (then working for American Cryogenics) who claimed he had welded shut one of the CSC dewars with three patients stuffed into it. He was hardly able to talk about it, and he described it as, “one of the worst experiences of my life.” He said he could smell the hair and flesh burning as he welded the inner can shut. I also called every cryogenic fluid distributor listed in the Yellow Pages in the greater Los Angeles area at that time. Everywhere, the story was the same “Do you know where Bob Nelson is? Can you tell us how to get in touch with him?” As Virginia Gregory, President of Gilmore Liquid said, “It’s not just the money he owes us for liquid nitrogen and demurrage; he also has a couple of our LS-160 LN2 delivery dewars!”

KEN WRITES: When you were making your accusations, Mike, why was none of this mentioned? The CUNY’s financial difficulties are well known. They suffered much of the same difficulties that plagued the CSC, patients’ families that weren’t paying, and leaky Cryo-Care capsules. You wrote half truths and flat out lies. I have documentation illustrating the REAL reason Mandel and DeBlasio left the NTCS.

MD’S RESPONSE: I left nothing out. CSNY and Cryo-Span paid their bills, took care of their patients well, and went out of business honorably and without litigation. Every patient was disposed of per the instructions from the next of kin, and was cremated or interred legally, and with dignity. No one was lied to or left to rot in their dewars. This was Steven Mandell as he once was:

This is what was left of Steve Mandell’s CC dewar after it was pulled out of Chatsworth. The top of the dewar has been removed with a cutting torch so the three decomposed bodies inside could be removed and interred. The forensic pathologist who was hired to help identify the remains said it took nearly a week to sort out the bones of the three people inside and free them from the “black goo” which had formerly been their soft tissues:

KEN WRITES: You laid the blame for the failure of DeBlasio failure to maintain his wife’s suspension of his wife. Bob was never involved with maintaining that vault. He had his own vault to tend to in Chatsworth. DeBlasio wanted out of the CSNY, and he didn’t want her shipped to another cryonics organization, so Bob did the logical thing and helped to build him his own vault where DeBlasio would have complete control. Bob went there at the request of two of the CUNY’s patients. His help in getting the mortuary to open up for the liquid nitrogen venders, and extending the time they allowed the CSNY to come up with the money owed was not the act of someone that was out to take those patients away.

I have the documents to prove that you were embellishing what happened with DeBlasio to discredit Bob Nelson and portray the NYCS as innocent victims. You sir, should acknowledge it and apologize for it.

MD’S RESPONSE: Throughout this response I’ve referred to the facility in Mt. Holiness Cemetery in Butler, New Jersey as the “Cryonic Interment East Coast Facility.” You claim that Bob Nelson had nothing to with that facility, and the loss of Ann Deblasio and the CSC patient from Beverly Hills was all Nick DeBlasio’s doing. You say that the facility in Butler, NJ was not a CSC or Cryonic Interment operation, and that Nelson was in no way involved beyond being what can best be described, per your account, as a good hearted, selfless soul, who just tried to help Nick Deblasio out of a bad spot due to CSNY’s insolvency. Well, neither you nor Bob Nelson can have it both ways. The fact is that I, and everyone else, took Bob Nelson at his word when he and CSC stated the following in the September 1971 issue of CRYONICS REVIEW, the official publication of CSC: “A second long-term cryonic storage facility is now operational in Butler, New Jersey. The facility was opened on September 17 by Cryonic Interment, Inc…The new facility, designed to accommodate 24 persons at liquid nitrogen temperature, compliments (spelling error theirs) the first long-term multiple-storage facility in operation in Chatsworth, California.” Here are scans of the original issue of CRYONICS REVIEW:

Here is a copy of the article from that issue of CRYONICS REVIEW

So was Nelson lying then, or is he (or you for him) lying now? What are we to believe? Perhaps we can best ascertain the truth by Nelson’s actions in sending a CSC patient from Southern California to be stored in the Mt. Holiness facility in December of 1972; and of his attempts to attract two other patients to CSC’s and Cryonic Interment’s care in 1972 and 1973? Maybe we might best be instructed as to Nerlson’s character and integrity (or lack of same) by the canceled CSC checks written to Frank Bucelli by Robert Nelson and to Elaine Bucelli by Robert Nelson? Who would have guessed in 1967 and 1968 that Robert Bucelli was in fact Robert Nelson, or that Elaine Bucelli was, in fact, Robert Nelson’s wife at the time? The papers I have, virtually the entire financial record of CSC from 1966 until its demise, show a picture of routine overdrafts, expenditures for dry cleaning, car towing, and utility bills (when CSC had no car, no facility and no uniforms). Below is but a small sample of what are hundreds of scans (and pages) of financial records that show the same dismal pattern of bounced checks and threats from creditors:

KEN WRITES: I anxiously await your response.

MD’S RESPONSE: You have it. Bob Nelson damaged the lives of many, if not most of the people he dealt with in cryonics. He arguably destroyed the lives of every patient he came into contact with, with the possible exception of James Bedford. I say “possible” because Nelson’s utterly unprepared and incompetent care of Bedford caused terrible injury which was shockingly visible when Bedford was examined during his transfer from the Galiso dewar to the Alcor Bigfoot dewar in May of 1991. His bloody face is a damning indictment of Bob Nelson – an indictment which remains unchanged (and unchanging) from that fateful day in January of 1967 when Nelson first betrayed the trust put in him by a patient and that patient’s family, and then took 135 pages to lie about it in WE FROZE THE FIRST MAN.

And yes, I have the photographs to prove it.

Mike Darwin

This message has been edited by Jonathan_Hinek on Jun 19, 2007 4:21 PM

From Jonathan Hinek:

Had to reconsider my decision           June 19 2007, 4:32 PM

After receiving a request from several parties and hearing a particularly sound argument about the current state of the ‘net, I’ve decided that the only responsible action to take is to remove the more graphic of the three images. I don’t think the gore is necessary, and such an image can only do damage if widely disseminated without proper explication. As always, I’m open to further input from Mike or anyone else who feels strongly about this.

From Mike Darwin:

No Problem     June 19 2007, 9:29 PM


I understand and have no problem with your redacting the image.

The Cold Filter

A forum dedicated to reporting on and discussing cryonics and cryo related topics.

From Long Life Lurker:

Paging Mr. Cryoken! Mr. Cryoken?!?…         June 20 2007, 1:20 PM

It turns out I was not alone with my concern about the photography in question. I certainly agree about transparency and disclosure as long as the process is considerate and careful. Should I presume these photos or others like them were presented when all this was the matter in court? A court of law is the venue I am most comfortable with when they are necessary to establish the facts. A current example of careful process is the People vs. Spector trial now being covered on CourtTV when they discretely avoid showing the explicit and graphic photos taken at the crime scene.As for the here and now, I am hoping for Mr. Cryoken’s prompt response to MD’s expansive Chatsworth review where the lessons are glaringly self evident. -LLL

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From Shipdit:

History and decisions June 20 2007, 5:01 PM

I feel that the original post in its entirety represents something extremely valuable.

History, edited by a perceived need for protecting others from unpleasantness becomes something different than history.


From Finance Director:

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Anyone wanting a copy of this picture, can email me.           June 20 2007, 11:53 PM

Some of us captured the original post before it was edited. I’d be glad to email the deleted picture, by file attachment, to anyone who did not get here in time and wants to see it. Use an email address capable of receiving a file attachment slightly under 600KB. Your email address, and that you emailed me, will not be divulged to anyone or retained by me.

This is not intended to mean that I disagree with Jonathan’s decision to remove it from the forum – he had to do what he felt is best and I support that.

Anyone can email me at: Redacted

This message has been edited by Finance_Department on Jun 20, 2007 11:57 PM

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This isn’t about protecting others from unpleasantness          June 21 2007, 9:54 AM

Although it may be a component. If my friend or family member was murdered, I probably wouldn’t want pictures of their bloody remains all over the internet. Even if those images did serve as some sort of reminder. However, that’s not the main reason I redacted the photo in question. Like Mike, I believe that his pictures can do some good, in the right place, and in proper context.

But what happens when such images are taken out of context? Once they’re digitally available, they will spread virally. People who are dedicated to discrediting cryonics will use them out-of-context to inflame others. Yes, I realize that this will, in all likelihood, happen regardless of what I do. The photo is undoubtedly being disseminated through e-mail as I write this. That doesn’t mean I want to be associated with it.

From Ken Bly:

My late late response  September 2 2008, 2:49 AM

I have ha neither the time nor the energy to respond to this lengthy post. However, in answer to FD’s persistent challenges, I decided to make the time tonight. It’s not as lengthy as I had anticipated originally. You don’t need to be particularly prolific to make a good argument.

“I asked Nelson about CSNY and he told me (this from notes made at the time) that their (CSNY’s) operation was “very substandard” and that “they are not storing the bodies properly. Henderson charges the family a fortune for liquid nitrogen, but he only keeps the capsules about 1/3rd full. That’s like medical malpractice because any cryobiologist will tell you that you have to keep tissue specimens completely covered in liquid nitrogen. I’ve explained this to Nick DeBlasio, and put him touch with our scientists at CSC, and I think he is going to move his wife (Ann) out of the Cryo-Span facility in the near future…CSNY is operating illegally and they do not have a secure underground facility which is immune to radiation in the event of nuclear attack, such as the Cryonic Interment facility will be here in Southern California…While he is far too much of gentleman to say so, Bob Ettinger’s, actions speak louder than words, and Bob always refers patients for suspension to CSC, not CSNY. I think the fact that the father of the movement refers patients to us should be all you need to know…It is widely known that Curtis Henderson has a serious drinking problem and that may be one reason that the storage at Cryo-Span is not what it should be…We charge less than a quarter of what Cryo-Span and CSNY charge a year for storage. We can do that because we have a lot more patients and because liquid nitrogen is cheaper here in California. In fact, sometimes I get liquid nitrogen for free because we get it by “bulk delivery” in a large tank-truck and I know the driver. If he has have LN2 still in the bulk tank at the end of his delivery route, then he will often just empty out the tank and we don’t have to pay for the extra nitrogen.”

Bob denies making these statements. In fact, he had a good relationship with Curtis fom the beginning. He gives Curtis and Saul a lot of credit for helping the CSC get started. They came to California at the beginning and gave some very helpful advise. Also, in a recent visit between Curtis and Bob, Curtis reminded Bob that the CSC sent the CSNY $1,000 of the money Bob got from selling We Froze the First Man. While there may have been light competition between the two societies, Bob did not trash mouth Curtis.

I will retract any past comments I’ve made regarding CSNY’s operation simply because I do not have adequate documentation other than a couple of letters from Mandell and one from Washington Memorial Park threatening to cut off LN2 supplies. Mike is obviously much more qualified to comment on CSNY operations than neither Bob nor myself.

“It took us nearly a day of uninterrupted work to free those two women from that dewar. A major reason for subjecting myself and Joe to that horror was to protect cryonics from what could have been, and in my opinion would have been, another scandal of Chatsworth proportions – coming right on heels of Chatsworth itself. The stench from the decomposing bodies was wafting over to the nearby homes (one of which you can see in the background) and the cemetery management was nearly hysterical and on the verge of calling the health department. Another reason was to give some closure to the son of the other woman in the dewar. He was decent, sincere, and wealthy professional who had considered CSNY, but had gone with Nelson instead because, as he told me at the time, of Bob’s claims of superior service, underground storage, and more competitive price. This patient died not on the East Coast or in the Midwest, but rather in Beverly Hills, CA on 13 November 1972 and was sent cross-country by Nelson to be stored in Cryonic Interment’s East Coast facility! Here was a man who truly was “lured away” from CSNY. And he was not the only one who was affected by Nelson’s lies.”

Bob did not have any control over the vault in Butler and he certainly never made a dime from it. He simply helped DeBlasio get the thing built. He also used the name “East Coast Facility” to bolster the image of the CSC for marketing reasons, but only on a couple of occasions. He was legally able to do that until DeBlaso finished paying Bob back for the vault )Bob fronted the money for the vault to DeBlasio). Questionable marketing tactic, sure, but Bob had no motivation to undersell one of your clients since he would have gained nothing from it. Bob recalls having the patient shipped to NYbut doesn’t remember for sure why. He believes it was because DeBlasio needed the funds to help out. DeBlasio would never have shared that capsule just to profit the CSC, Hell, He wouldn’t share it with Mandell, and he was banging her.

“In December of 1972 CSNY cryopreserved another patient. This woman was the first patient I cryopreserved, and her wellbeing and continued survival were incredibly important to me. Solely on the basis of Nelson’s assertion that he could store this patient for less money, and more securely underground in a “permanent” facility, her family decided to have her transferred to Nelson’s East Coast Facility in Butler, New Jersey. The MVE dewar which had been on order for her was, upon completion, shipped to Mt. Holiness in Butler, where it sat, still crated at the side of the road, near the Cryonic Interment East Coast Facility for many months. The patient’s relatives (truthfully, I believe) testified that Nelson took their money (around $2,000, if I recall correctly) and never showed up to “encapsulate” their mother. This family then made the decision to bury their mother, something they had wanted to do from the start, but which Nelson gave them an excellent excuse to follow through on. Sadly, this patient had provided ~$30,000 for her long term care, but to no avail.”

BS. According to Curtis Henderson’s own deposition, the patient’s daughter and son were nut cases and a pain in the ass. She wanted Curtis to spread the payments for the capsule and services out over time. Curtis refused. Instead, HE sent her to Bob, telling her that he would likely be willing to do it. Curtis wanted to get rid of them! I don’t have the testimony in my possession right wow, but I’d be happy to get it. Mike Perry and Bob both have copies. Also, Bob agreed to go to NY and make arrangements to check out the condition of the patient and possibly have her shipped to California. He was paid up front for his travel expenses. When he got to NY he called the son. The son told him that he wanted nothing to do with cryonics and that they were all “fucking crazy”., which is consistent with the son’s testimony. Bob could have still checked to see what kind of shape the patient was in, but what would be the point? The lawsuit was started by the daughter because Bob didn’t have the money to pay the full $2,000 back to her. He offered to do it in payments, but she refused to accept. Again, Curtis wanted to get rid of the daughter and son. This is his own testimony under oath.

“Maybe we might best be instructed as to Nerlson’s character and integrity (or lack of same) by the canceled CSC checks written to Frank Bucelli by Robert Nelson and to Elaine Bucelli by Robert Nelson? Who would have guessed in 1967 and 1968 that Robert Bucelli was in fact Robert Nelson, or that Elaine Bucelli was, in fact, Robert Nelson’s wife at the time? The papers I have, virtually the entire financial record of CSC from 1966 until its demise, show a picture of routine overdrafts, expenditures for dry cleaning, car towing, and utility bills (when CSC had no car, no facility and no uniforms). Below is but a small sample of what are hundreds of scans (and pages) of financial records that show the same dismal pattern of bounced checks and threats from creditors:”

This means nothing. Have you never bounced a check? I worked with Bob for years and managed his TV shop. He operated it, as he did his cryonics operation, as a sole proprietorship. He often paid for materials, services and even payroll out of his own pocket. He would sometimes repay himself from the business by writing himself a check. There were times when funds were low and he didn’t have the money in his personal account to cover, so small checks sometimes bounced. It wasn’t something that happened every day, but it happened. Again, have you never bounced a check? This doesn’t say anything about his character. Running a micro business can be difficult, but he managed to do so for many years, and did OK.

“Bob Nelson damaged the lives of many, if not most of the people he dealt with in cryonics. He arguably destroyed the lives of every patient he came into contact with, with the possible exception of James Bedford. I say “possible” because Nelson’s utterly unprepared and incompetent care of Bedford caused terrible injury which was shockingly visible when Bedford was examined during his transfer from the Galiso dewar to the Alcor Bigfoot dewar in May of 1991. His bloody face is a damning indictment of Bob Nelson – an indictment which remains unchanged (and unchanging) from that fateful day in January of 1967 when Nelson first betrayed the trust put in him by a patient and that patient’s family, and then took 135 pages to lie about it in WE FROZE THE FIRST MAN.”

Bob did not do the perfusion of James Bedford himself. Dante Brunol and Robert Prehoda did the perfusion and Bob assisted. Did they betray the patient and his family? If Bob lied about it in We Froze the First Man, where is the outrage from the people he wrote about in the book? i would think that everyone from Robert Ettinger to Robert Prehoda would have been pretty pissed off, and we would have heard from them a long time ago.

A small handful of people; The Chamberlains, Mike Darwin, and Charles Platt, are bent on discrediting everything Bob Nelson and the CSC did, even to the point of discrediting themselves. If Bob Nelson’s operations were completely negative, if everything he ever did was criminal, neglectful, deceitful and disgraceful, why did the Chamberlains and others stay with him so long? Why don’t people like Robert Ettinger, Marshall Neal, Joe Klockgether, and many others loser to his operations condemn him? Why just these few? The trial hurt cryonics. Bob Nelson got in over his head and did some questionable things trying to do the honorable thing and keep his patients in suspension. These people want desperately to distance themselves from the trial and bob Nelson by discrediting everything he did. That is cheap and blatantly unfair. Unfortunately the Chamberlains, Platt have a great deal of influence among the cryonics community, and what they say carries a lot of weight.

I’m nobody in the cryonics community, but I’m here to set the record straight the best I can for those who are willing to listen. I set out to help Bob write a book about what happened and I was appalled by some of the things I read on the internet. My goal is and has always been to find out what happened and why, weather my enquiries are good for bob’s reputation or not. Obviously not everything he did was positive. Conversely, not everything he did was bad. Those who try to discredit all that he did without acknowledging at lease SOME positive harm their own credibility, much more than I am harming mine by defending what Bob did right.

From Mike Darwin:

Re: Do nothing good; say nothing bad! (Final) September 3 2008, 10:53 AM
Ken writes:

*”I asked Nelson about CSNY and he told me (this from notes made at the time) that their (CSNY’s) operation was “very substandard” and that “they are not storing the bodies properly. Henderson charges the family a fortune for liquid nitrogen, but he only keeps the capsules about 1/3rd full. That’s like medical malpractice because any cryobiologist will tell you that you have to keep tissue specimens completely covered in liquid nitrogen. I’ve explained this to Nick DeBlasio, and put him touch with our scientists at CSC, and I think he is going to move his wife (Ann) out of the Cryo-Span facility in the near future…CSNY is operating illegally and they do not have a secure underground facility which is immune to radiation in the event of nuclear attack, such as the Cryonic Interment facility will be here in Southern California…While he is far too much of gentleman to say so, Bob Ettinger’s, actions speak louder than words, and Bob always refers patients for suspension to CSC, not CSNY. I think the fact that the father of the movement refers patients to us should be all you need to know…It is widelyknown that Curtis Henderson has a serious drinking problem and that may be one reason that the storage at Cryo-Span is not what it should be…We charge less than a quarter of what Cryo-Span and CSNY charge a year for storage. We can do that because we have a lot more patients and because liquid nitrogen is cheaper here in California. In fact, sometimes I get liquid nitrogen for free because we get it by “bulk delivery” in a large tank-truck and I know the driver. If he has have LN2 still in the bulk tank at the end of his delivery route, then he will often just empty out the tank and we don’t have to pay for the extra nitrogen.”

Bob denies making these statements. In fact, he had a good relationship with Curtis fom the beginning. He gives Curtis and Saul a lot of credit for helping the CSC get started. They came to California at the beginning and gave some very helpful advise. Also, in a recent visit between Curtis and Bob, Curtis reminded Bob that the CSC sent the CSNY $1,000 of the money Bob got from selling We Froze the First Man. While there may have been light competition between the two societies, Bob did not trash mouth Curtis.*

This simply isn’t true, any of it. Curtis Henderson is still very much alive and he does NOT agree with these remarks. Nor does he consider Bob Nelson a “friend” or anything other than, and I quote, “a liar and a fraud.” It is not necessary to take my word on this matter. If Ken Bly and Johnathan Hinek, or some other reasonable and dispassionate 3rd party is willing, I will arrange for you to speak with Curtis by telephone and you can ask him these questions yourself. I request only that the conversation be recorded (with all parties’ consent) and made available to the principals as part of the historical record. If Curtis wishes a wider distribution, that is up to him. I need not be present on the call but would like a copy of the recorded call.

It is very easy for someone to say, as Bob and Ken have (sic), “Why, I think Curtis Henderson is my friend and that he and I have the utmost respect for each other.” That would be the equivalent of someone saying of me, “Mike Darwin and Bob Nelson are great friends, they’ve never exchanged a harsh word and Bob has always been forthcoming when he has spoken to Mike by phone. He seems very committed to cryonics today, is signed up, and Mike thinks the past is the past and let’s all just try to get along.” It is true that Bob and I have never exchanged harsh words, that he has been forthcoming on the few phone calls we’ve had, and that he is apparently signed up with CI. It is not the case I consider him a friend or feel the past is the past and should be forgiven absent genuine remorse, acceptance of personal responsibility, and a full and honest accounting of the misdeeds. I believe in forgiveness, but not in whitewashing and certainly not in establishing as the moral standard in cryonics that you can do anything terrible, immoral, destructive, deceitful or dishonest with no adverse consequences from the cryonics community as long as you don’t *say& anything unpleasant, uncomfortable, upsetting, un-aesthetic, or otherwise politically incorrect or as being perceived to “hurt” the image of cryonics or (fill in the blank) the image of the ______________. cryonics organization.

There are two people and just about only two people (other than I) who were principals to the events re Nelson and CSNY from 1968 to 1975 who have not spoken out in print. Other than asking them to speak for the record, and facilitating that to the extent possible, I do not know what more I can do. I can be reached at: m2darwin@googlemail.com.

*I will retract any past comments I’ve made regarding CSNY’s operation simply because I do not have adequate documentation other than a couple of letters from Mandell and one from Washington Memorial Park threatening to cut off LN2 supplies. Mike is obviously much more qualified to comment on CSNY operations than neither Bob nor myself.*

Fair enough, and my sincere thanks.

*”It took us nearly a day of uninterrupted work to free those two women from that dewar. A major reason for subjecting myself and Joe to that horror was to protect cryonics from what could have been, and in my opinion would have been, another scandal of Chatsworth proportions – coming right on heels of Chatsworth itself. The stench from the decomposing bodies was wafting over to the nearby homes (one of which you can see in the background) and the cemetery management was nearly hysterical and on the verge of calling the health department. Another reason was to give some closure to the son of the other woman in the dewar. He was decent, sincere, and wealthy professional who had considered CSNY, but had gone with Nelson instead because, as he told me at the time, of Bob’s claims of superior service, underground storage, and more competitive price. This patient died not on the East Coast or in the Midwest, but rather in Beverly Hills, CA on 13 November 1972 and was sent cross-country by Nelson to be stored in Cryonic Interment’s East Coast facility! Here was a man who truly was “lured away” from CSNY. And he was not the only one who was affected by Nelson’s lies.”

Bob did not have any control over the vault in Butler and he certainly never made a dime from it. He simply helped DeBlasio get the thing built. He also used the name “East Coast Facility” to bolster the image of the CSC for marketing reasons, but only on a couple of occasions. He was legally able to do that until DeBlaso finished paying Bob back for the vault )Bob fronted the money for the vault to DeBlasio). Questionable marketing tactic, sure, but Bob had no motivation to undersell one of your clients since he would have gained nothing from it. Bob recalls having the patient shipped to NYbut doesn’t remember for sure why. He believes it was because DeBlasio needed the funds to help out. DeBlasio would never have shared that capsule just to profit the CSC, Hell, He wouldn’t share it with Mandell, and he was banging her.*

Ken, READ what you have written above, really read it. You say:

a) *“He also used the name “East Coast Facility” to bolster the image of the CSC for marketing reasons, but only on a couple of occasions.”*

This would be comical if the subject and its consequences weren’t so tragic. So, if I understand your position correctly: it is OK to lie perniciously “once or twice” but not two or three times? It is OK to leave everyone in the cryonics community AND the world at large believing a seriously misleading statement from September 1971 until now, or whenever it was (some months ago) when Nelson finally informed the world that the Cryonics Society of California’s East Coast Facility was not really that at all, and was, in fact, ooops, just a “questionable marketing tactic.” Let’s see, 2008 minus 1971 = 36 years. That’s as good as, “I am not a crook,” “I did not have sex with that woman,” and “that depends upon what the definition of is is.” Morally in my book it is *much worse.*

What does someone have to do to provoke even the slightest moral outrage or concern from the cryonics community? And why does it matter? Well, it matters because Nelson was the opening act of “clinical cryonics” and his deceit and misdeeds were not only tolerated, they were praised and rewarded. This is symptomatic of a deep psychopathology in cryonics that continues to this day. As my understanding of this phenomenon has become more sophisticated, I’ve come to realize that there are two main types of (in my opinion) sociopathic personalities that currently infest the clinical aspect of cryonics. I call them “pod people” because they can (as in the case of Nelson) look and act like real cryonicists, and Nelson’s type even has the remarkable ability to be liked and admired, this despite truly terrible behaviour. In fact, this species of pod person is often well spoken of by the same people they have hurt repeatedly, and without remorse.

The second type of pod person is the “hired hand;” individuals who enter cryonics as paid “professionals” to provide clinical services. This type has been around almost from the beginning as well, but in recent years it has started to become more common. Not all non-cryonicists who have worked as professionals in cryonics are pod people, or do harm. Far from it; many have been extraordinary caregivers showing high competence, a willingness to take personal and professional risks, and who deliver technically rigorous care.

Most people who see ads for jobs in cryonics either are not interested, check it out and decide it is not for them, actually try out the job and decide it is not for them, or take the job and find it rewarding intellectually and emotionally, if not financially. With the advent of high paying jobs in cryonics, yet another type of job seeker has been attracted; the person who could care less about cryonics or cryonics patients, but who nevertheless takes the job and fights tenaciously to hold on to it. The reasons for wanting the job, and liking it, are that there is no feedback, virtually no caseload, and in short, high pay for doing little or nothing. Psychologically healthy people invariably leave such situations, especially when they involve highly emotional, as well as medically and psychologically controversial and stressful experiences, such as is the case with cryonics.

The situation of dying people who are hoping and counting on a technology which you, as an employee and provider, do not believe in, or worse still, hold in contempt, would be intolerable for almost anyone. Almost – and there’s the rub. Because the kind of person who will take such a job and “fake” concern while providing dismal care is neither commonplace nor psychologically healthy. They are, at a minimum, low-grade sociopaths, and when they luck into the tiny world of cryonics where they are well paid, have little work, and enjoy the need, and often the admiration and gratitude of their victims, it is the functional equivalent of turning a pack of wolves loose on the Galapagos Islands. Cryonicists are completely defenceless because they desperately need the services these people claim to competently provide; which in turn makes them less critical and more willing to suspend normal levels of scrutiny. Additionally, the average cryonicist is not medically sophisticated, and has little ability to judge what constitutes good care. *In fact, the problem goes deeper still because there is no consensus nor standards for good care, let alone any criteria for what constitutes an error, bad judgement, negligence or even pathological wrong doing.* Finally, the patients who are hurt can not only not complain they can’t even demonstrate any signs or symptoms of the abuse they’ve suffered.

It must be a dream come true for this kind of psychopath; the psychosocial equivalent of being able to beat your wife or abuse a child endlessly and with absolutely no detectable sequelae – and thus no possible adverse consequences. I believe that the failure to act when Nelson behaved as he did, starting with Bedford’s cryopreservation, was a crucial and damaging mistake that has dogged cryonics to this day. I’ve begun to organize these ideas into a long article and a slide presentation. The latter is designed to try and show, by analogy, and in a blackly humorous way, that these pod people exist, and that they are much like the pod people in the SF classic _Invasion of the Body Snatchers._ Their characteristics and a shortlist of the damage they have done to cryopatients is summarised in the following images:

b) *“Bob recalls having the patient shipped to NY but doesn’t remember for sure why.”*

He doesn’t recall why????? Nelson did not exactly have a huge practice; he was not a physician or surgeon with hundreds or thousands of patients. Nor was he was a businessman with thousands of customers or clients. Excluding Dr. Bedford and Clara Dostal, he had 11 patients in his sorry career in cryonics. The one in question was the mother of a successful and well respected Los Angeles attorney who I had substantial dealings with regarding disposition of his mother’s remains. If Nelson does not recall why he sent this woman to New Jersey, he must be either forgetful beyond comprehension, negligent, uncaring, or lying. I can’t imagine any reasonable person believing such incredible nonsense. This was a human being, or at very least human remains which had to be transported on dry ice; and that required complex paperwork and coordination. She was not a pair of trousers dropped off at the drycleaners! What kind of psychopath would claim he has no idea why he shipped a cryonics patient, for whom he had accepted responsibility and been paid for, to a facility he now claims he had no control over her care or wellbeing and who he now states he put into the hands of a man who had no experience or expertise in the field, and who was (unarguably) proved to be incompetent to provide safe cryogenic care?

Give us all a break!

c) You write: *“DeBlasio would never have shared that capsule just to profit the CSC, Hell, He wouldn’t share it with Mandell, and he was banging her.”*

How do you know “he was banging her?” All I know is that Nick told me he and Pauline Mandel had been dating, and briefly considered marriage. I have no idea if they engaged in intercourse, and unless you have evidence to support this contention, I think you should consider retracting this statement.

*”In December of 1972 CSNY cryopreserved another patient. This woman was the first patient I cryopreserved, and her wellbeing and continued survival were incredibly important to me. Solely on the basis of Nelson’s assertion that he could store this patient for less money, and more securely underground in a “permanent” facility, her family decided to have her transferred to Nelson’s East Coast Facility in Butler, New Jersey. The MVE dewar which had been on order for her was, upon completion, shipped to Mt. Holiness in Butler, where it sat, still crated at the side of the road, near the Cryonic Interment East Coast Facility for many months. The patient’s relatives (truthfully, I believe) testified that Nelson took their money (around $2,000, if I recall correctly) and never showed up to “encapsulate” their mother. This family then made the decision to bury their mother, something they had wanted to do from the start, but which Nelson gave them an excellent excuse to follow through on. Sadly, this patient had provided ~$30,000 for her long term care, but to no avail.”

BS. According to Curtis Henderson’s own deposition, the patient’s daughter and son were nut cases and a pain in the ass. She wanted Curtis to spread the payments for the capsule and services out over time. Curtis refused. Instead, HE sent her to Bob, telling her that he would likely be willing to do it. Curtis wanted to get rid of them! I don’t have the testimony in my possession right wow, but I’d be happy to get it. Mike Perry and Bob both have copies. Also, Bob agreed to go to NY and make arrangements to check out the condition of the patient and possibly have her shipped to California. He was paid up front for his travel expenses. When he got to NY he called the son. The son told him that he wanted nothing to do with cryonics and that they were all “fucking crazy”., which is consistent with the son’s testimony. Bob could have still checked to see what kind of shape the patient was in, but what would be the point? The lawsuit was started by the daughter because Bob didn’t have the money to pay the full $2,000 back to her. He offered to do it in payments, but she refused to accept. Again, Curtis wanted to get rid of the daughter and son. This is his own testimony under oath.*

I have no doubt that your account of Curtis’ attitude in this matter is more or less correct. I’d be fascinated to see the copies of the lawsuits and court actions.

I never met Richard Dostal, but I did meet his sister Claire Halpert who was, in my opinion, a most unpleasant woman. Considering the circumstances, I’m not sure I can blame her (she must have felt like she just stepped into a Twilight Zone episode), but I’m not inclined to think warm thoughts about her, either.

BUT, SO WHAT????? Curtis Henderson had to deal with these same “nut cases” and, to the best of my knowledge, he did not receive a penny from them until the MVE dewar was sold to Ray Mills, Jr. at Mt. Holiness Cemetery. Now, consider that while Curtis was not paid for perfusing, cooling and storing Clara Dostal on dry ice for many months, he did not abandon her or let her thaw out and decompose. Everything else is completely irrelevant. Rational and responsible alternatives would have been for Nelson to call the Medical Examiner or the Health Department, both of whom deal with abandoned human remains all the time. New York and New Jersey have a well developed system in place (as do most metropolitan areas in the US) for disposing of bodies abandoned by relatives, or in cases where no family can be found. In New York, it is City Cemetery, which is more commonly called “Potter’s Field,” and it is located on Hart Island in the Bronx; out on Long Island Sound. Burials are done with inmate labor under supervision of the New York State Department of Corrections. This is not a recent development, and since the Hart Island facility first opened in 1869, ~750,000 burials have taken place there. My knowledge of Hart Island is due to the fact that another cryonics patient who was being stored by family who could no longer support his care, and where there were no funds for burial or cremation, was interred in Potter’s Field on Hart Island *still ensconced in his (then ~$8,000) MVE dewar!*

When you write: *“Bob could have still checked to see what kind of shape the patient was in, but what would be the point?”* Do you think we are all idiots? Why don’t you answer that question yourself?

In the meantime, here are a few of my own answers, and I suspect they reflect those of most of the people reading this:

1) Commonsense; what kind of sociopathic personality is required to just leave a woman’s body lying around because the family was unhappy or even “nuts”? That is precisely why morticians and cemeterians are licensed and go to jail if they do something like that! The answer is, this kind of sociopath (in fact, this fellow went to jail):


*“Every funeral director for 100 miles did business with the Tri-State Crematory on the assumption that the owners were doing their job of transforming dead bodies into ashes. But today, horrified authorities discovered decomposing evidence that the furnace at the crematory had not worked for years.

After a dog walker stumbled over a skull on Friday, law enforcement officers discovered at least 120 rotting corpses in sheds and on the ground near the crematory, and state officials said that that figure could double by the time the area is fully excavated. Some of the bodies had been there for years and were nearly skeletal, while others, fresh from the funeral home, still bore toe tags.

Human bones, weathered white, were scattered through the woods like leaves, skulls mixed with leg bones in a ghoulish jumble that one state trooper compared to a scene from a Stephen King novel. An infant’s body was found in a box in the back of a rusting hearse.

Some bodies had become mummified and may have been at the site more than 20 years, said Dr. Kris Sperry, Georgia’s chief medical examiner. Nearly two dozen coffins that had once been buried were also found on the ground, Dr. Sperry said, and in some cases their embalmed contents had been dragged out and left exposed to the elements for years. It was unclear why those bodies were at the site.
Officials said there was no foul play involved. But even hardened law enforcement officers were left shaken and nauseated by the sight that greeted them in the sheds.
”There were bodies stacked like cordwood, just discarded and thrown in a pile,” said Vernon Keenan, assistant director of the Georgia Bureau of Investigation. ”After 30 years in law enforcement, you think you’ve seen everything. And then you see something you can’t even imagine.”

Dr. Sperry, who deals with corpses every day, said nothing in his experience prepared him for what he saw today.

”I have to say, the utter lack of respect in which they were piled on top of one another was very disturbing,” he said.”*

This was a scandal that disturbed the entire nation. It really makes no moral difference whether it was 1 body one 1,000 bodies handled in this disrespectful manner; and it is the same kind of action you dismiss as casually as you might excuse someone from dropping an empty soda can or food wrapper on the street!

2) He could have contacted the Medical Examiner or the Public Health Department both of whom have routine experience dealing with and disposing of bodies where there is no known next of kin or the family is indigent and cannot afford to pay for disposal of the body. New York and (sometimes) New Jersey use the City Cemetery, commonly called Potter’s Field, on Hart Island in the Bronx onLong Island Sound. Since it began operations in 1869, more than 750,000 burials (estimate) have been made on Hart Island. My familiarity with Hart Island came about as a result of a cryonics case where the family was indigent and the patient was interred on Hart Island still in situ in a ~$8,000 MVE dewar (in 1974 dollars!).

3) He could have contacted the family and followed up to be sure that the remains were disposed of legally and with dignity. Again, anyone with a lick of sense and a picogram of concern about the damage that might result to cryonics from such a callous and negligent act would have taken steps to ensure that the body was properly disposed of. He would certainly not just “walk away and forget about it!”

*”Maybe we might best be instructed as to Nelson’s character and integrity (or lack of same) by the canceled CSC checks written to Frank Bucelli by Robert Nelson and to Elaine Bucelli by Robert Nelson? Who would have guessed in 1967 and 1968 that Robert Bucelli was in fact Robert Nelson, or that Elaine Bucelli was, in fact, Robert Nelson’s wife at the time? The papers I have, virtually the entire financial record of CSC from 1966 until its demise, show a picture of routine overdrafts, expenditures for dry cleaning, car towing, and utility bills (when CSC had no car, no facility and no uniforms). Below is but a small sample of what are hundreds of scans (and pages) of financial records that show the same dismal pattern of bounced checks and threats from creditors:”

This means nothing. Have you never bounced a check? I worked with Bob for years and managed his TV shop. He operated it, as he did his cryonics operation, as a sole proprietorship. He often paid for materials, services and even payroll out of his own pocket. He would sometimes repay himself from the business by writing himself a check. There were times when funds were low and he didn’t have the money in his personal account to cover, so small checks sometimes bounced. It wasn’t something that happened every day, but it happened. Again, have you never bounced a check? This doesn’t say anything about his character. Running a micro business can be difficult, but he managed to do so for many years, and did OK.*

I’m not talking about an occasional bounced check; I’m talking about a routine practice that went on for years. Here are but a few examples:

I am not where I can access the CSC records, but I can provide you with many more pages of what you see exemplified above.

*”Bob Nelson damaged the lives of many, if not most of the people he dealt with in cryonics. He arguably destroyed the lives of every patient he came into contact with, with the possible exception of James Bedford. I say “possible” because Nelson’s utterly unprepared and incompetent care of Bedford caused terrible injury which was shockingly visible when Bedford was examined during his transfer from the Galiso dewar to the Alcor Bigfoot dewar in May of 1991. His bloody face is a damning indictment of Bob Nelson – an indictment which remains unchanged (and unchanging) from that fateful day in January of 1967 when Nelson first betrayed the trust put in him by a patient and that patient’s family, and then took 135 pages to lie about it in WE FROZE THE FIRST MAN.”

Bob did not do the perfusion of James Bedford himself. Dante Brunol and Robert Prehoda did the perfusion and Bob assisted. Did they betray the patient and his family? If Bob lied about it in We Froze the First Man, where is the outrage from the people he wrote about in the book? i would think that everyone from Robert Ettinger to Robert Prehoda would have been pretty pissed off, and we would have heard from them a long time ago.*

-Great point!- To my knowledge Dante Brunol did at least one more case under illegal and dismal circumstances. What happened to him after that, I have no idea. Curtis Henderson has repeatedly told me that Bob Ettinger knew there had been no perfusion, and that he and Ettinger had looked at Bedford’s face when Bedford was still on dry ice (Henderson and Ettinger had flown out to LA for the press conference announcing Bedford’s cryopreservation). Why didn’t any of these people say anything? I don’t know the answer to that question with the exception of two cases; Curtis Henderson and Robert Prehoda. Curtis has said that to his considerable regret he said nothing because the first freezing had finally happened and the consensus (unspoken) was to just smooth it over and do better next time. Do I think this was a mistake? Absolutely. Do I think it was immoral? Absolutely. While it may not have been possible to publicly disclose what had happened for many reasons (patient/family privacy, litigation, etc.) that would not have, and should not have, stopped the matter from being dealt with privately, honestly and aggressively inside the cryonics community – there and then. Certainly, you don’t pat the doctor on back who has just botched his first surgery due to a near total lack of preparation and competence, and then refer 11 more patients to him!

As to Prehoda, to his credit he did speak out, but only years later. It was too little too late, but I give him enormous credit for his honesty and for his obviously genuine concern about Bedford when he stood in front of his dewar in Fullerton, and with more sincerity that I have heard from most involved in the sorry affair of Bedford’s care in 1967, or lack thereof, said (sic), “I really hope he makes it.”

That Nelson lied in We Froze the First Man is without question. That he lied at the press conference is also without question:

“A small handful of people; The Chamberlains, Mike Darwin, and Charles Platt, are bent on discrediting everything Bob Nelson and the CSC did, even to the point of discrediting themselves. If Bob Nelson’s operations were completely negative, if everything he ever did was criminal, neglectful, deceitful and disgraceful, why did the Chamberlains and others stay with him so long? Why don’t people like Robert Ettinger, Marshall Neal, Joe Klockgether, and many others loser to his operations condemn him? Why just these few? The trial hurt cryonics. Bob Nelson got in over his head and did some questionable things trying to do the honorable thing and keep his patients in suspension. These people want desperately to distance themselves from the trial and bob Nelson by discrediting everything he did. That is cheap and blatantly unfair. Unfortunately the Chamberlains, Platt have a great deal of influence among the cryonics community, and what they say carries a lot of weight.

I’m nobody in the cryonics community, but I’m here to set the record straight the best I can for those who are willing to listen. I set out to help Bob write a book about what happened and I was appalled by some of the things I read on the internet. My goal is and has always been to find out what happened and why, weather my enquiries are good for bob’s reputation or not. Obviously not everything he did was positive. Conversely, not everything he did was bad. Those who try to discredit all that he did without acknowledging at lease SOME positive harm their own credibility, much more than I am harming mine by defending what Bob did right.*

Again this nonsense: First, Marshall is dead; he died from motor neuron disease some years ago. Marce Johnson is ill with Alzheimer’s. I can tell you that when I spoke with Paul Porcasi (a CSC Director and long-time associate of Bob’s in cryonics) at the last Alcor Conference some months ago in Phoenix, he had absolutely nothing positive to say about Nelson and when I asked him how Nelson managed to pull off his deceit for so long, he simply shook his head and said (and I quote), “You just had to be there. It was incredible.”

At the time Nelson was operating there were, generously, maybe 50 people seriously active in cryonics. In fact, it was not until after 1983 that Alcor had more than 50 signed up members!

Most of the activists who had dealings with Nelson are either dead, incapacitated, or simply refuse to discuss what was an unpleasant and in some cases financially costly experience in their lives. Even given the heavy mortality in this cohort, I know of at least six people alive and well today who were activists at that time and who share my opinion of Nelson. If you want names, ask me by email. Considering only ½ or less of the activists at that time had dealings with Nelson, and considering the high morbidity and mortality in this cohort as a whole, 6 people is a very large number indeed.

As to Bob Ettinger, he is still around and I guess the answer is to ask him.

Marce did ask me to speak for her, and she gave me the CSC records and personally handed me the letter reproduced below. What she said was (quote), “This letter speaks for itself. Bob was a trusted friend and someone that I believed in. How could anyone with any humanity write a letter like this to me when I was very concerned about what had happened to the patients, and what could happen to me and my family in terms of personal responsibility, because I had taken over the Presidency of CSC at Bob’s request? Please see to it that this letter becomes public when the time is right.”

The time is right.

When the letter below was written, all but two of the patients at Chatsworth had long been thawed out and were rotting away. According to Nelson’s sworn testimony (Los Angeles Superior Court case C-161229; Supplemental answers to interrogatories …, 14 (July 22, 1980) the “capsules had failed” sometime around mid-1974 (http://www.alcor.org/Library/html/suspensionfailures.html) .
Only a person’s worst enemy or a monster (or both) would write the letter below from Nelson to Marce Johnson dated 15 April, 1977. This letter was sent to a woman who Nelson to this day states did him no harm, helped him and CSC faithfully, and whom he considered a “dear friend.”

That this letter is a holographic document I am very, very thankful for. It is as if Nelson were speaking these words on tape, because they are in his own hand (I have provided a typed transcription following the letter.) I have also included scans of the document whereby Marce took over the Presidency of CSC on 11 October, 1974; the same year Nelson has testified that the majority of the CSC patients had thawed out, including former friends and associates of Marce’s such as Russ Stanley and Helen Kline.


17 April, 1977
Dear Marce,
I just received your letter and felt I must respond immediately. It upset me to learn that you feel I am or should be in hiding. My guess is that (sic) your still feeling the pressures of that lying ghastly written (sic) suppena (subpoena) . But I thought we discussed and dismissed that matter for what it was, a totally untrue document. The only reason I avoided it all was at Mrs. G.* (sic) advise because that would give them the opportunity to search in other areas in their lying money grabbing search.
I feel no need or desire to hide from anyone. I am still renting the apartment with Holly* as when I last saw you and can be reached at this number I gave you at the time (399-2664) Since we last talked my time has been consumed with my mom having cancer and her losing her 52 year old husband to heart attack 2 weeks after her breast removal. I’ve been going through an intensive electronics retraining. The years with cryonics left me with a large gap in my knowledge and ability to earn a living thru electronics repair. In addition I am maintaining the facility – have installed a new alarm system and ordered an additional capsule.
My interest and commitment to cryonics is still very great. However I am unwilling to spend or waste time trying to interest the masses in the subject. As Ettinger so correctly phrased it, “Before you can interest people in cryonics you must interest them in life” and that is not a crusade I am qualified or care to take on. I know you know all of this, but I just feel like repeating it so at least there is no confusion in your mind as to where I stand, or what I am doing at the present time. So to summarize. I am maintaining the facility I am interested in and working in the storage end of cryonics. I am and have been here (at Hollys**) since my return from Hawaii and would like to talk to you at any time. You are one of my dearest friends and prime movers in this effort to extend our precious life. I look forward to hearing from you as soon as you and I can arrange a time and place.
Endless Best Wishes,
Believe me,
(Signature) Bob Nelson
P.S. I will write Mr. Fallon** regarding the capsule inquiry immediately. Thanks.
* “Mrs. G refers to Stella Gramer who was the legal counsel for CSC Mrs Gramer was influential in CSC on almost every level, and we understand that it was due largely to her financial support that Cryonic Interment (CSC’s sister for-profit company) was able to construct its underground facility at Chatsworth. Mrs. Gramer was very active in CSC in the early days of cryonics and she can be regarded as a pioneer cryonicist. Mrs. Gramer was brutally murdered on February 7th; an unemployed scriptwriter named Thomas DeSoto is being held in connection with her death. Apparently DeSoto and his mother, June Nelson, had been living with Mrs. Gramer for the past five years. Mrs. Gramer had practiced law in California for 61 years and was still actively practicing law at the time of her death at 84 years of age. Mrs. Gramer was described by friends and associates as being “spry and energetic, very much involved with her law practice.” She was reported to be the oldest practicing female member of the California Bar. (see: http://www.alcor.org/cryonics/cryonics8304.txt)

Presumably referring to Holly Douglas Martin, daughter of Donald Wills Douglas, Sr. The e founder of Douglas Aircraft Company (Douglas Aircraft became McDonnel-Douglas in 1967) . Ms. Douglas married the insurance salesman Fred K. Martin in a well publicised “first” cryonics wedding where the “till death do us part” portion of the vows was omitted from the ceremony.

*** Refers to a letter from Bill Falloon of the Cryonics Society of South Florida enquiring about manufacturers of patient storage as well as pricing and availability.


Mike Darwin

Posted in Cryonics History, Philosophy | Leave a comment

Does Personal Identity Survive Cryopreservation?

By Mike Darwin


Someone who wants to understand the critical technical, social, political or personal issues involved in cryonics may well turn to any of several FAQ’s (Frequently Asked Questions) sites hosted by the various cryonics organizations.[1],[2],[3] As someone who was responsible for writing some of the answers to the technical questions used in these FAQs, I was interested to find upon revisiting them for the first time in many years that they contained little more scientific and technical information than was available more than a decade ago. Of greater concern was the realization that in some cases, the rapid and sustained advances in neuroscience and cryobiology over the past two decades offer the possibility for far more definitively bounding answers to questions such as, “under what conditions  is long term memory (LTM) and personality likely to survive (or not survive) cryopreservation, or be badly degraded?”

Beyond satisfying the intellectual curiosity of the public, these issues are a key component to informed consent for individuals considering cryopreservation for themselves, or for a family member, or other person for whom they may have the responsibility and authority to make such a decision. Furthermore, if it can be demonstrated that the biochemical and structural basis upon which memory and personality (personal identity) rest are degraded or destroyed by some cryopreservation techniques, while being preserved by others, then the issue of what treatment to choose within the sphere of human cryopreservation procedures becomes paramount.

Figure 1: At top above (A) is a typical transmission electron micrograph (TEM) of cerebral cortex tissue at 10,000 x magnification. The slice from which this image was created was ~50 nanometers (nm) thick and was cut from a minute block of brain tissue (B) in which the water was replaced with a polymer that was subsequently plasticized. Generation of useful 3-dimensional images usually requires ~100 scanned, high resolution photographs (C) for input into the tomographic program.

In the mid-1980s, neuroscientists studying the mechanics of how memory is encoded in the brain began to develop techniques precisely analogous to those used in medicine to create 3-dimensional images of tissue structure – but in this case, on the nanoscale as opposed to the macro-scale images produced from serial, uni-dimensional x-rays of tissue with Computerized Tomographic Scanning (CT-Scanning). Two techniques have been developed to allow such 3-dimensional nanoscale imaging of brain tissue: Electron Microscopic tomography[4, 5] and Ultrathin Serial Section Transmission Electron Microscopy (USSTEM).[6],[7] This latter technique consists of making ~ 100 serial sections of tissue (in this case of brain tissue), of 40 to 60 nm thickness and imaging them with conventional Transmission Electron Microscopy (TEM). The resultant images are captured on conventional high resolution photographic film[1], digitized using a standard flatbed scanner, and then subjected to computer processing using a standard PC running MS Windows to yield a 3-dimensional image which can be further manipulated, based on available software and the investigators’ objectives.[8] The process of USSTEM is shown in Figure 1. The serial images obtained using TEM are aligned and stacked, at which point software is used to render a 3-dimensional representation of the imaged tissue (Figure 2 and Figure 19).[9]

Figure 2: Sample volume reconstruction and analysis. Top, a section of the series (A) showing the sampling frame (blue) and identified synapses (red). The left and top edges of the frame are exclusion edges. A synapse that contacts an exclusion edge is marked with a yellow contour. Middle (B), the stack of serial sections for the aligned series is depicted in semi-transparent gray. After alignment, the sections form a volume with an irregular boundary due to the different transformations applied to each section. Inside this irregular volume, a rectangular prism or brick (purple) is defined as a reference volume for making density measurements. Finally, further processing (C) allows extraction of the desired reconstructed images from the sampled tissue block. In C, above, a set of 11 dendrite segments has been reconstructed from the serially TEM imaged tissue volume. The dendrites appear in the three-dimensional configuration that they have in the reconstructed volume. They are colored to help distinguish the individual segments and their synapse bearing spines. The red dendrite is a segment from an interneuron, as determined by the frequency and clustering of shaft synapses and the lack of mature-looking dendritic spines. [Fiala J.C., Harris K. M. (1999) Dendrite Structure. In Dendrites (eds. G. Stuart, N. Spruston, M. Häusser), Oxford University Press, in press.][9]

When consideration is given to the kinds of research cryonics organizations have funded over the past two decades,[10], [11] it is astonishing that they have not conducted in-house, nor commissioned extramural studies of this kind on brain tissue subjected to the cryopreservation techniques they are currently using (under both ideal, and the actual clinical conditions in which they are being applied). This is especially the case because the volume reconstruction system needed to perform this kind of imaging is freely available on-line as a Windows (2000, 95, 98, and NT) application called Serial EM (sEM) Align, and is straightforward to use. The sEM Align program was developed with the funding of the Human Brain Project and is available online at http://synapses.bu.edu./.  [If cryonics organizations have retained existing tissue blocks from brain cryopreservation studies conducted in the past, these could easily be further sectioned, and the needed TEM photographs for tomographic reconstruction generated.]

Defining the Elements of Personal Identity – and it’s Destruction

What constitutes personal identity is a matter of considerable controversy and contention, and there may in fact be no single answer to the question that applies universally.[2] An excellent discussion of these issues, including a superb bibliography on the ‘problem’ of personal identity is available here: http://plato.stanford.edu/entries/identity-personal/.

Despite the uncertainty attending the definition of personal identity, it is possible to define and explore the biological and structural elements that comprise it. This is the case because only a limited number of biochemical and structural elements are candidates for encoding memory and personality, and it is now increasingly possible to image both this chemistry and structure.[12],[13],[14],[15],[16],[17],[18],[19, 20],[21] Similarly, without being able to succinctly define personal identity, we nevertheless find ourselves in the position of being able to determine when it is irretrievably lost by using the criterion of “information-theoretic death” as applied to the physical structures which encode and instantiate memory and personality. Information-theoretic death is the destruction of the human brain (or any cognitive structure capable of constituting a person) and the information within it to such an extent that recovery of the original person is theoretically impossible by any physical means. The concept of information-theoretic death (ITD) arose in the 1990s in response to the problem that as medical technology advances, conditions previously considered to be death, such as cardiac arrest, become reversible and are no longer considered to be death.[22] The criterion of ITD will be used to judge whether or not personal identity survives any given cryopreservation modality throughout this discussion.

“Information-theoretic death” is intended to mean death that is absolutely irreversible by any technology, as distinct from clinical death and legal death, which denote limitations to contextually-available medical care rather than the true theoretical limits of survival. In particular, the prospect of brain repair using molecular nanotechnology raises the possibility that medicine might someday be able to resuscitate patients even hours after the heart stops. The term “information-theoretic” is used in the sense of information theory.

Figure 3: DNA, the molecular starting recipe for constructing the individual.

The molecular foundation upon which personal identity is built is the genomes – the nuclear genome, which is comprised of genetic material from both parents – and the mitochondrial genome, which is inherited from the mother in the form of the mitochondria in the cytoplasm of the maternal oocyte. In particular, the instructions for constructing the individual that are present in the form of the nuclear DNA most powerfully contribute to the fundamental structural composition of the individual.

It is important to understand that DNA is a recipe, not a blueprint.[23] Nuclear DNA does not specify where every cell, let alone every molecule in the human body will be placed, just as a recipe for a cake does not specify where each gas bubble in the cake will be, what their precise relationship will be to each other, or even how many bubbles there will be. The proof of this in humans is seen in the case of identical twins. Twins do not share the same fingerprints, the same retinal (or cerebral) blood vessel arrangements, and where one twin is homosexual, there is only a 38% chance that the sibling male twin will be gay, and a 30% chance of shared sexual orientation in the case of female twins.[24],[25],[26],[27]

Additional determinants of brain and body structure occur during fetal development as a result of influence from the maternal biochemical environment; maternal circulating nutrient and hormone levels, harmful or beneficial maternal transmission of chemicals from the environment, and so on.

Similarly, there are biophysical influences from the environment during the growth and development of the child – and continuing through life, which may shape personal identity. Once maturation is reached, such influences are likely to be of less significance in shaping brain structure and biochemistry critical to memory and personality, although there are clearly exceptions to this rule.[3] During and after the completion of neurogenesis in the brain (~ 2 years of age)[28] the primary determinants of memory and personality will be experiential, and will take the form of long-term memories encoded in the molecular structure of the brain. It is the complex interaction of these “recorded” experiences with the hardware encoding and processing them, that constitute personhood. The nuclear genome continues to be of importance in that it is responsible for maintaining the neuronal machinery that encompasses the person, and it is even critical to the elaboration of proteins needed to modify brain structure in order to create and maintain long-term memories.[19]

Freezing Damage

In order to understand if personal identity survives cryopreservation, it is first necessary to understand the nature and extent of the damage that results from cryopreservation, via either freezing or vitrification, and under a range of clinically relevant conditions.

Figure 4: The water-sodium chloride-glycerol phase diagram above shows the enormous increase in salt concentration that cells are exposed to in the absence of cryoprotection (red line) and in the presence of increasing, but still modest concentrations of the cryoprotective agent (CPA) glycerol. Absent cryoprotection, there is a ~12 fold increase in the concentration of dissolved solids cells are exposed to by -20oC; the point at which no more water can be converted into ice upon further cooling.[29] The effect of this increase in the extracellular solute load on cell volume is shown in Figure 5, below.

A typical cartoon rendering of the effects of freezing at slow to moderate rates is shown in Figure 5, below. This scenario is accurate in that it correctly shows that under these conditions, ice forms first outside of cells, and the ice crystals consist of pure water.[30] Ice begins forming outside of cells rather than inside of them for at least two reasons. First, the concentration of dissolved materials in the water inside cells is much higher than that present in the water outside of the cells (in the extracellular space). These concentrated materials, primarily salts, such as phosphates and potassium chloride, exert a small amount of antifreeze activity, depressing the freezing point of the intracellular milieu about a degree Celsius (C) below that of the extracellular fluid.[31, 32]

The second factor in play is that for ice to begin forming at temperatures at or just below 0oC, it is necessary for molecules known as nucleators to be present.[33] Nucleators, or nidi as they are sometimes called, mostly consist of bacterial proteins and poorly characterized inorganic molecules, and serve as a template for ice growth to begin. This has the effect of raising the freezing point of water from -40oC to 0oC. It is believed that the intracellular space does not contain these nucleating agents.[34]

Figure 5: Typical representation of how freezing proceeds in cells and tissues. Ice begins forming outside cells, forming crystals of pure water. The salts and other solids that were formerly dissolved in the crystallized water are forced into a progressively smaller volume of unfrozen solution. This increase in the concentration of solids dissolved in the extracellular fluid osmotically extracts water from the cells, causing them to shrink. At ~ -20oC no further water can be converted into ice and the interior of the cells remains in an unfrozen state – a highly concentrated solution of cell proteins and salts, from both inside and outside the cells. With further cooling this electrolyte gel will be converted to a crystal free glass at ~ -100oC

Once ice formation begins, as previously stated, it forms crystals of pure water, and this means that solids that were previously dissolved in the extracellular water being converted into ice are excluded from the ice crystals, and become dissolved in the progressively smaller volume of water that remains unfrozen. This has the effect of increasing the concentration of dissolved salts and proteins present outside of the cells, and as a result, water is removed from the cells by the increased extracellular osmotic pressure generated by the rising concentration of salts.[35],[36] As the temperature is reduced, and progressively more ice forms, more and more water is osmotically extracted from the cells until an equilibrium state is reached, and all the ice that can form has done so.[37] The result is what you see at right in Figure 5, above: severely dehydrated, shrunken cells surrounded by extracellular ice.[38] The interiors of such cells contain such highly concentrated salts and proteins that ice cannot form there. As cooling proceeds, eventually, at a temperature of ~ -100oC, this very viscous electrolyte gel that now comprises the intracellular space transitions from a liquid state to a solid state – in this case to a non-crystalline solid, a glass.[29]

Chemicals that provide cryoprotection are typically antifreeze compounds that are virtually identical in their action to that of ethylene glycol and propylene glycol, the chemicals used in automobile radiators, and to winterize plumbing in recreational vehicles to protect them against freezing damage.[36],[35],[39] These antifreeze compounds work not only by decreasing the point at which a mixture of the agents and water will freeze, but also by reducing the amount of ice that forms when freezing does occur.[40] They do this by two mechanisms: a) by the ‘bulk effect’ of taking up so much space in the solution that they physically interfere with the interaction of water molecules with each other, by providing a kinetic obstacle, and b) by so strongly hydrogen bonding to water that they prevent the water from continuing to be converted into ice, once a certain amount of ice has been formed. These mechanisms of action are termed “colligative cryoprotection.”[36],[35],[41] Instead of the entire volume of solution freezing, only part of it does, whilst the rest becomes a thick, un-freezable liquid that, upon further cooling, solidifies into a crystal-free and molecularly immobile glass (see Figure 6).[42] The more of the colligative cryoprotectant molecule(s) present in the solution (or in the cells or tissues), the less ice is formed (Figure 7).[36],[35]

Figure 6: At left a rabbit kidney that has been frozen following treatment with ~ 40% cryoprotectant agents. The kidney was submerged in solution that did not have enough cryoprotective agents present to allow it to vitrify. The kidney has a chalky, opaque appearance due the presence of large amounts of ice in the tissue. At right is a kidney that has been perfused and equilibrated with sufficient cryoprotectant to allow cooling to -140oC with no ice formation.  Because this kidney has no ice crystals in it to refract light, it remains translucent and appears unfrozen – which is in fact the case – even though it has been converted to a solid, glassy state.[43]

Figure 7: The fraction of a solution that is converted to ice upon freezing is a function of the amount of colligative cryoprotectant agent (CPA) present, as shown at left, above: the higher the CPA concentration, the smaller the fraction of the solution that is converted to ice at any given temperature. By contrast, in cryopreservation by vitrification the concentration of cryoprotectants is sufficiently high to prevent any ice formation during cooling, regardless of how low the temperature of the solution is cooled to. [Graphic courtesy of Brian Wowk, Ph.D., of 21st Century Medicine, Inc., http://www.21cm.com/]

If enough antifreeze chemicals are present in the solution, no ice forms, and the solution is said to be vitrified (converted into a glassy state) if it is cooled below its solidification point.[44] Since crystallization does not accompany solidification of solutions when they vitrify, the point at which the solution transitions from a liquid to a solid state is called the Glass Transition Point, which is abbreviated Tg. The difference between vitrified and frozen tissue is readily apparent to the naked eye, as can clearly be seen in Figure 6, above.[43]

Figure 8: A ribbon model depicting the kind of conformational changes typically seen in protein denaturation.

The obvious advantage that vitrification enjoys over freezing is the absence of ice formation. Because the molecules that comprise the solution both inside and outside the cells remain in an unorganized state that is virtually indistinguishable from its aqueous state, there is no mechanical injury to cells due to ice growth dehydrating and compressing them – and tearing, or otherwise degrading the connections between cells. The cells are also spared the many fold increase in intra- and extra-cellular ion (salt) concentration. This latter advantage is important, because one way in which cells are injured by freezing is at the molecular level. Many of the proteins that comprise the workhorses of cellular activity, including enzymes, DNA, RNA and the structural proteins critical to the cell maintaining its shape and membrane integrity, require the presence of water to maintain their functional structure.[45]

The water normally suspending and surrounding these proteins provides “conformational support” and is essential to many proteins maintaining their functional shape. When too much water is removed from the medium suspending proteins, the proteins may become denatured. What this means is that that the string of amino acids that make up the backbone of the protein can become unstable, and lose its necessary folding configuration, as seen in Figure 8, above. Since a protein is made up of a “bead work” of amino acids forming a long chain, it is often possible for that chain to be folded, or configured, in different ways. Unfortunately, usually only one folding configuration allows the protein to function in the lock and key fashion it requires in order to function properly – or at all.

When very high concentrations of salts or cryoprotective chemicals replace the native cellular water, protein can become completely denatured (Figure 8), or partially denatured. Sometimes this is reversible, but most often it is not, and the only solution to protein denaturation is for the cell to synthesize a replacement protein. However, if all of a species of protein that is essential to cellular metabolism is rendered inactive by denaturation, then the cell does not have the opportunity to restart metabolism, and thus replace the damaged protein(s).

Figure 9: Cartoon of cell membrane structure.The plasma membrane is composed of a lipid bilayer made up primarily of phospholipids with cholesterol interdigitated in the interior of the phospholipid bilayer. A large variety of proteins, carbohydrates, and glycolipids are studded into, or decorate the membrane and serve as receptors, signal transducers, molecular transporters, pores, ion channels and pumps. At physiological temperatures the membrane lipids exist in a disordered, highly liquid state which is converted to a more organized gel state upon cooling to ambient temperature (~ 20oC). Further cooling can result in profound phase change in the membranes lipids resulting poration of the membrane and/or the redistribution or exclusion of embeded proteins and other structures essential to normal cell function.[46]

Of course, cells are not just made up of proteins; they are also composed of lipids (fats) and carbohydrates. The lipids, in combination with the proteins, constitute the primary structural elements of the cells: the intracellular organelle membranes and the plasma membrane that separates the intra- from the extra-cellular spaces. The cellular membranes are the walls, floors and tanks that make up the organized structure of the cell. However, far from being passive dividers or containers, the cellular membranes are incredibly complex molecular machines which are studded with proteins that perform a vast range of functions, from the mundane to the nearly miraculous (Figure 9).[47],[48] The cell membrane selectively controls the passage of nutrients, ions, water and a nearly endless array of signaling molecules into and out of the cell. Embedded in the membrane are structural support elements, and complex protein and protein-lipid complexes that act as molecular gatekeepers and message senders and receivers, facilitating communication between the cell and its environment.

Vitrification Damage

Both freezing and vitrification can damage cell membranes and cell proteins in the same ways. The antifreeze chemicals that comprise vitrification solutions are not water, and the very property that makes them useful in tightly binding water and preventing it from forming ice, makes then unable to fully pinch hit for water biochemically.[4] As a consequence, replacement of too much of the cellular water content with cryoprotectants in order to secure vitrification upon cooling, can result in protein denaturation.[49] Additionally, the colligative compounds used to achieve vitrification have the potential to solubilize or dissolve membrane components,[41] and they may also destabilize the lipid bilayer that comprises the cell membranes – or further facilitate its disturbance during cooling.

As seen in Figure 9, the cell membrane is composed of a laminar bilayer of phospholipids and cholesterol, studded with proteins, glycolipids and carbohydrates which serve as regulatory portals, signal transducers, and transporters for wastes and for molecules essential  for metabolism and structural maintenance. This bilayer is normally lamellar – a smooth arrangement of phospholipids with the hydrophilic polar heads pointing out and the hydrophobic portion forming the core of the membrane bilayer. These phospholipids and cholesterol which comprise the membrane are mostly present in the liquid state at body temperature. However, these lipids, independent of the cellular water, undergo freezing, or phase change when cooled. Many cell membrane lipids freeze at or near room temperature, and almost all cellular lipid species are frozen at high subzero temperatures (i.e., above -20oC).[50],[51]

Figure 10: Above, top, shows a false-color rendering of the normal configuration of membrane lipids and the membrane protein sodium-potassium-ATPase in a bacterial cell membrane. The membrane exhibits a smooth, lamellar character, and there are only a few aggregated and displaced particles of protein evident (yellow granules). In B, at right above, there is evidence of an alteration in membrane structure after the cell has been incubated at ~ -6oC for 1 hour in the presence of 20% w/v dimethylsulfoxide (Me2SO4). The membrane has developed a pebbly appearance and there are many extruded granules of protein on the membrane surface.

The lower illustration (above) is a computer rendering of  various lipid phase transitions in a model system (Langmuir trough), some of which result in perforations of the normally lamellar membrane structure.

Lipid phase change can result in a variety of alterations to membrane structure, and thus function.[52], [53] Reorganized lipids in the membrane may open up holes or pores which allow the leakage of water and ions into or out of the cells.[54] Cooling, independent of freezing, can also irreversibly alter the structure of glycolipids and lipid-protein complexes, rendering them inactive. Phase change in the membrane can also result in the precipitation, relocation, or extrusion of membrane proteins critical to cellular function, as seen in Figure 10.[55] Figure 10A shows the normal configuration of a cell membrane after rapid cooling to a stable, deep subzero temperature. The smooth lamellar character of the membrane is conserved, and very few of the particles (yellow) of sodium-potassium-ATPase protein are seen adjacent to the embedded lipoprotein structure (pink) in the membrane. In Figure 10B it is evident that the membrane has lost its smooth lamellar character and has undergone phase change. There is extensive relocation of the sodium-potassium-ATPase from the interior domain of the membrane to the surface, as well as aggregation of the protein into visible particles.

TEMs of membranes subjected to cooling to below the phase transition point of the lipids comprising them show the presence of long cylinders, which resemble the inverted hexagonal phase formed by some lipid-water dispersions under conditions of extreme dehydration. In this phase, water is found in long narrow cylinders on a hexagonal array, wherein each cylinder is surrounded by the hydrophilic moiety of the lipids. This morphology creates pores in the membrane forming a semipermeable barrier. A variety of other topological alterations in membrane structure have also been reported as a result of cooling.[56],[46],[57] Lateral phase separations may also occur in the fluid state, and under conditions of low hydration, whether from the removal of water from the cellular milieu by ice formation, or as a consequence of replacement of a large fraction of the cellular water with cryoprotectants, islands of protein free membrane are observed in TEMs. Further, phase separation of membrane components may occur, which result in one phase which is enriched in highly hydrating lipid species, and another which is enriched in weakly hydrating lipid species. The significance of this alteration is that the inverted hexagonal phases can most easily be formed by weakly hydrating lipids in the absence of protein – and the change from the lamellar to the hexagonal phase compromises the relative impermeability of the membrane to ions, and even to larger molecular species.[58]

The longer a cell is held at temperatures intermediate to the freezing points of membrane lipids, and stable, very low subzero temperatures (i.e., below – ~50oC), the more likely lipid phase change is to occur, and the more extensive such changes will likely be.[59] The chemical composition of the medium inside and outside the cells may also act to either stabilize, or destabilize membrane lipids, with respect to phase change.[60] So, while these changes can and do occur in the course of freezing, they are likely to be more extensive and more biologically significant in organs (or other large systems) subjected to vitrification, where there is necessarily prolonged exposure to high concentrations of cryoprotectants in the presence of high subzero temperatures, before the system is cooled to sufficiently to arrest these adverse alterations in membrane morphology.[61],[62]

Figure 11: Peri-capillary tear in the parenchyma of the cerebral cortex as a result of hyperosmotic dehydration secondary to cryoprotective perfusion prior to vitrification. The space resulting from the dissection of the neuropil from the capillary basement membrane has been colored with a light purple tint.

There is also osmotic injury which occurs during brain cryopreservation employing currently available vitrification techniques. The permeability of cell membranes to most cryoprotectants is very slow when compared with water. As a consequence, these osmotically active CPAs extract water from the intracellular space more rapidly than they can equilibrate with it, given the constraints imposed by the toxicity of these agents: namely, that they must be introduced at low temperatures (sometimes well below 0oC) and that the exposure time at these relatively high temperatures must not be too long. The relative impermeability of colligative cryoprotectants to brain tissue is not, as is commonly misunderstood, a function of the blood brain barrier (BBB). Most colligative CPAs freely cross the BBB because they are lipid soluble. Rather, it is due to the kinetics of water and CPA movement across the individual brain cell membranes. The multiply membrane wrapped myleinated axons that comprise the white matter pose a special diffusion barrier, in this respect. The cerebral dehydration that results from perfusion with high molarity CPA solutions causes occasional peri-capillary tears (Figure 11) as well as infrequent small tears within the brain parenchyma.


Figure 12: At left, above, is a flask of vitrification solution cooled to its solidification point of ~ -135oC. The solution is unfrozen and solid – a glass. At right, is what happens when the solution is further chilled to ~ -160oC; the solution has extensively fractured. The center insert shows a rabbit kidney equilibrated with 4M glycerol and then frozen to -196oC. It has extensively fractured, as well. The degree of fracturing seen in the photos above is worst case. Since the time this phenomenon was discovered, considerable work has been done to reduce the number and severity of fractures. This has been accomplished by slowing the rate of cooling during and after Tg, as well as providing for a period “stress relaxation” by annealing, or holding at a temperature near Tg. [Solution in flasks images are courtesy of Brian Wowk, Ph.D., of 21st Century Medicine, Inc., http://www.21cm.com/]

A type of injury common to cryopreservation by both freezing and vitrification is fracturing injury.[42, 63],[64],[65]When cryoprotective solutions, or organs loaded with them are cooled to significantly below the glass transition point of the CPA-water solution, internal stresses begin to build up.[66],[67] Since CPA-water glasses are inherently weak (and most tissues are little stronger), the result is cracking, or fracturing of the solution, or of the organ, as seen in Figure 12, above. Various protocols of controlled, ultra-slow cooling, and of annealing by holding the temperature steady for an interval at or near Tg, help to reduce the number and size of fractures, but no technique has yet been identified which eliminates them. Even storing just below Tg still causes some fracturing to occur.[42, 68]

Biological versus Electromechanical Machines

It is probably no accident that a large fraction of the people recruited to cryonics since its inception have been engineers, mathematicians, computer scientists, programmers, and, in general, physical science types.[5] One likely reason for this is that there is a fundamental difference in the way biological ‘machines,’ and electromechanical machines are structured and operate. Almost all electromechanical systems may be fairly described as solid state – even those in existence before the era of “modern electronics” and the advent of the transistor. By solid state, what is meant here is that virtually all their components are, literally, solid at their normal operating temperatures.

Figure 13: Living cells are not electro-mechanical machines comprised of solid-state, rigid parts which fracture, or break into discrete, easily identifiable pieces of debris when mechanically damaged.

A consequence of this is that it is possible to take a 21st Century mobile phone, or even a 17th century mechanical clock, and hit them with a sledgehammer, and the end result would broadly be the same: a collection of solid pieces of varying sizes and shapes that just sit there – and of course, neither the phone nor the clock would be functional. However, all the pieces would continue to exist unchanged – and they would retain their individuality and unique identity (Figure 12). And such would be the case indefinitely, as long as they are protected from the elements (moisture, oxidation, corrosion) and are kept at a temperature below their melting or combustion points.

Figure 14: Even the simpler cells in the human body are surprisingly complex, as is the case with the red blood cells (RBCs), as seen above.  At left, (A) is an electron micrograph of RBCs with a 2 micron scale bar present – each RBC is ~ 8 microns in diameter. Red cells lack nuclei and the complex interior structure of other somatic cells; however their structure is still enormously complex. As can be seen in (B) at left, the cytoskeleton, the molecular framework that gives the RBC its unique biconcave shape and deformability, is comprised of an intricate web work of proteins. The membrane itself (C) is studded and interdigiated with a wide array of complex proteins arranged into pores, pumps, and signaling devices.[48]

Biological systems are not solid state devices, and they operate in very different ways from such instruments. The core of biological systems is the membrane; and, as previously noted,  membranes in living systems are not just passive walls or “compartment makers.” They are the engines of chemistry and action in living systems (Figures 9, 14 and 16). They have enormous complexity and they derive a great deal of their unique ability to function as living systems from their liquidity and plasticity.[48] A physical analogy in the everyday macro-world would be that of soap bubbles (Figure 15). Cell membranes are very much like soap bubbles and they behave in broadly similar ways when stressed. If a cell  is osmotically stressed by shrinking or swelling it too much, it does not behave like a glass sphere and shatter into discrete pieces, which can be collected and reassembled. Rather it buds and ‘blebs’ and behaves like what it is, a liquid. And if it is stressed enough, it comes apart into little droplets and into smaller ‘cells;’ blebs and vesicles that have formed from the original membrane (Figure 17).

Figure 15: The soap bubble is a tolerable working analogy to the cell membrane – both the plasma membrane that encases the cells – and the intracellular membranes that bound the cellular organelles, such as the nuclei and the mitochondria, exhibit the same liquid based, space enclosing behavior.

Before disintegration or blebbing of the cell membrane occurs in response to stress (e.g., osmotic, temperature reduction, dehydration, chemical destabilization), the structure of the membrane can undergo reorganization in many ways, and the proteins embedded in the membrane may be rearranged as well. This is true not just for the plasma membrane that encloses the cell, but also for the membranes that comprise the cellular organelles. In fact, it is just such a rearrangement of mitochondrial membrane structure that underlies some of the damage that occurs in ischemia.[69] [6] Freezing causes enormous biophysical stress to the plasma membrane, and to organelle membranes, and some of the response to this stress is to radically alter membrane structure.

Figure 16: Far from being simple, passive, devising walls, cell membranes are complex biological machines consisting of structural elements, pumps, channels, and gated pores. In turn, these various functional units are comprised of complex proteins that translate the energy generated by the cell, and stored in ATP, into the work required to regulate ion homeostasis, transport nutrients and pump out wastes.

In the worst case, the cell membranes disappear as the structures they were, and reappear as new structures; droplets of membrane material, brand new micro-cells, and so on.[70] And they shed structures that were embedded, or enclosed in them; thus the explanation for the debris fields seen in frozen-thawed tissues that are inadequately cryoprotected.

Figure 17: At left (A), the shadow of a hepatocyte is superimposed over the debris field (B) remaining after the cell was exposed to a hypertonic medium yielding approximately the same osmotic stress as would be experienced during freezing to -20oC (i.e., increase in incubating medium osmolality from ~310 mOsm to 3,720 mOsm). The cell has partially lyzed and has formed numerous large blebs (B) containing cytoplasmic material, as well as smaller plasma membrane vesicles devoid of interior structure. The intracellular organelles are largely unrecognizable with the exception of a few swollen mitochondria (M) and the cell nucleus (N). At right (C-D) hypertonicity-induced plasma membrane blebs and vesicles on the surface of a frog oocyte. The blebs and vesicles vary in size and were induced by exposure to a solution of approximately 3x normal tonicity (800 mOsm) – a fourth of the hyperosmotic stress imposed as a result of freezing to -20oC.[71]

Because biological systems are not solid state devices, if they are damaged badly enough, they do not remain as discrete, broken pieces waiting to have their pre-injury, functioning structure inferred from the debris. And it is important to understand that some of the “re-morphing” that goes on during the cryopreservation process occurs as a consequence of the enormous osmotic and mechanical stresses imposed by ice formation – not as consequence of thawing (see Figure 17, above). Further, as previously noted, there are significant changes to membrane structure, such crystallization of the lipids that occur solely as a result of cooling, and completely independent of freezing. To return to the mobile phone analogy, it would be as if the phone were made up of liquids and gels encased in soap bubble membranes, and the device was crushed. Crushing is thus a much better analogy to use when describing cryoinjury to biological systems, than is breaking or shattering.

Imagine a soap bubble with an exquisitely detailed picture embedded into its surface. A picture made up of millions of tiny pixels comprised of colored micro-particles. If you burst the bubble, some of the bubble wall material will return to a simpler, all-fluid state, and some of it may reform into new bubbles. But in any event, the picture is gone, and what’s more, it is not obvious that the image can be inferred from the puddle of particles in liquid, and the new bubbles that result. In fact, given our current understanding of physical law, inference of the image that was on the surface of the bubble before it burst is not possible.


Figure 18: Simple schematic of a neuron and its axon, dendrites and synapses. The dendritic arbors that grow out of the neuronal soma and from the axon generate hundreds of thousands of synapses (up to 1 million per neuron) that serve as the signal switching mechanisms allowing inter-cellular communication and encoding LTM.

Figure 19: At left above, the cytoskeleton of a typical cerebral cortex neuron from the hippocampus. A representative dendrite has been circled in red and is shown in greater detail in Figure 20, below. This image was created using Rotary shadow electron microscopy of a cultured, wild-type, hippocampal neuron. The plasma membrane has been removed, allowing a detailed view of the underlying cytoskeleton. At right (above) is an artist’s cutaway rendering of the axon, showing the cytoskeleton, and microtubules that carry skeletal proteins, and other nutrients from the cell soma, to the dendrites and synapses. [Stern, S, Debre, E,  Stritt, C, Berger, J, Posern, G, Knöll, B. A nuclear actin function regulates neuronal motility by serum response factor-dependent gene transcription. The Journal of Neuroscience, April 8, 2009, 29(14):4512-451: http://www.jneurosci.org/cgi/content/short/29/14/4512]

A typical cerebral cortex neuron in a mammal may have as many as one million synaptic interconnections with its neighboring neurons, yet each one is distinct, and will have different configurations of membrane proteins and structure at any instant in time. These synapses can cover the entire body of the neuron, including the dendrites, where they are observed as “synaptic spines,” using various kinds of electron microscopy. Electron microscopic examination with 3-dimensional reconstruction of a microscopic block of brain tissue demonstrates that these synapses are present at very high density in relation to each other.[72],[73],[74] In Figure 20 the incredible density and exquisitely complex synaptic connections of three dendritic spines branching from three different axons is shown. Each point of color (excluding green) is a functional point of synaptic contact. The topology and apposition of these structures must be conserved during cryopreservation in order to preserve LTM.

Figure 20: A: A 10 µ segment of pyramidal cell dendrite from stratum radiatum (CA1) with thin, stubby, and mushroom-shaped spines. Spine synapses colored in red, stem (or shaft) synapses colored in blue. The dendrite was made transparent in the lower image to enable visualization of all synapses.[75] B: Graphic reconstruction (i.e. manually shaded serial contour tracings) of dendritic spines arising from three dendrites (D1, D2, D3) participating in synaptic glomerule in thalamic ventrobasal nucleus. Some of spines are branched (asterisk). Multiple macular synapses of different afferent origin are marked in blue, red and orange. Extensive reticular adherent zones free of synaptic vesicles are marked in green. (Rat, thalamic ventrobasal nucleus.) (Adapted from Spacek and Lieberman 1974)[76]

Figure 21: At left above is a three dimensional block of brain hippocampal tissue tomographically reconstructed from hundreds of slices of tissue 0.25 micron thick, using the same mathematical algorithms used in computerized tomography (CT) scanning employed in medical imaging. In the image above, a single dendrite has been isolated from the tissue block to show the number and configuration of its synapses. There are approximately 100 billion neurons in a typical 1.4 kg human brain, with an aggregate average of 0.15 quadrillion synapses.[77, 78] At right is a representation of a neuron having undergone synaptic remodeling in response to the encoding of long-term memory; with new synaptic connections highlighted in yellow.

It is critically important, especially for the engineers, information technology, and computer scientists who are reading this to understand that the brain is not a computer, but rather, it is a massive, 3-dimensional hard-wired circuit. It does not use programming, addresses, or coding; and in engineering terms it most closely resembles pre-digital computer integrated circuits. Such circuits were constructed and wired for a discrete purpose and they did not function as multiple use processors. Similarly, the neuronal circuitry in the brain shows no evidence of using the biophysical equivalent of “addresses,” such as are used in digital computers. Each neuron has a single output axon which cannot select a receiver. Before addresses can work, they have to be agreed upon between the sender and the receiver, and such a function is problematic to have been generated as a result of biological evolution via natural selection.[7]

And of course, without addresses, there can be no ordered set of bits that carries information; and consequently no bytes, and no record. Coding, as is used in computers, is thus not possible: no location can be given to send or retrieve information from, and information cannot be moved from neuron to neuron. Another consequence of the inability of the brain to process information using programming, addresses and coding, is that information cannot be put side by side and compared. This means that information must be encoded and retrieved at the same location. A consequence of these insights is that, from an information processing standpoint, the brain is most properly viewed as a massive 3-dimensional homogenous memory array, with each memory location having its own processor, and every node and connection a site-dependent, dedicated purpose. Acute losses of circuit elements (neurons) are thus of far greater significance than are the loss of processors in a digital computer because they represent loss of the memory information they contain.

Molecular and Ultrastructural Basis of Long Term Memory

Of concern in the setting of cryonics is the nature of long term memory (LTM) and its likely response to the biophysical changes that may be imposed as a result of freezing and vitrification under different conditions. Several mechanisms are currently understood to be in play in the formation of LTM. The earliest of these is long-term potentiation (LTP), which is an enduring strengthening of signal transmission between two neurons that results from stimulating them synchronously.[79] LTP is but one of many mechanisms that facilitate the ability of chemical synapses in the brain to change their strength, and thus exhibit what is known as synaptic plasticity.[80] LTP appears to be the first step by which memories are encoded in the brain and it operates by modification of synaptic strength in response to artificial stimulation (simulated inter-neuronal signaling) via the delivery of carefully modulated electrical pulses, or naturally, as a result of multi-pass filtered and integrated somatosensory signaling, generated as a result of life experience.[81],[82],[83]

Figure 22: Artist’s rendering of some of the structural elements underlying long term potentiation (LTP): neuronal plasma membrane (NMP), dendrite (D), bouton (B), mitochondria (M), chemical synapse (CS), neurotransmitter vesicles (V), dendritic spine (S), cytoskeleton (C) and golgi apparatus (G). ). A necessary ‘defect’ to this rendering is that it shows far more extracellular space and much lower density of synapses than are actually present in the mammalian brain. A single axonal arbor is capable of sprouting tens of thousands of synapses.

LTP has been the focus of a decade’s long investigation because it has in common with LTM rapid induction in response to experience or artificial stimulation, rapid induction of the synthesis of new proteins, the property of being associative in nature, and both LTP and LTM can last for many months in vivo in the free ranging animal.[79],[84] It has been posited that LTP may be the mechanism for encoding both broad classes of learning and memory: ranging  from the most basic conditioned-responses present in unicellular organisms, to procedural learning, such as mastering a musical instrument, or learning how to drive a car, through the high-level cognitive memory involved in intellectual tasks such as understanding a scientific theory, comprehending complex social relationships, and recognizing individual faces and facial expressions.[79]

At the level of individual neurons, LTP enhances synaptic transmission by lowering the threshold for two neurons, one presynaptic and the other postsynaptic, to communicate with one another across a synapse. The precise molecular mechanics of how this alteration in synaptic sensitivity to signaling occurs are still not fully understood. Under laboratory conditions (usually employing brain slices in vitro) LTP occurs primarily as a result of alterations to the biochemistry and structure of the postsynaptic cell’s sensitivity to signals received from the presynaptic cell.[82] These signals occur secondary to the electrochemical stimulation of the presynaptic neuron, which results in the release of neurotransmitter chemicals (i.e., dopamine, serotonin, norephenephrine, etc.,) which activate neurotransmitter receptors present on the surface of the postsynaptic cell.

Figure: 23: Simplified schematic of the expression of LTP: An increase in calcium within the dendritic spine binds to calmodulin (CaM) to activate CaM Kinase II, which undergoes autophosphorylation, thus maintaining its activity after calcium returns to basal levels. CaMKII phosphorylates AMPA receptors (AMPARs) already present in the synaptic plasma membrane, thus increasing their single-channel conductance. CaMKII is also postulated to influence the sub-synaptic localization of AMPA receptors, such that more AMPA receptors are delivered to the synaptic plasma membrane. The localization of these “reserve” AMPA receptors is unclear, and thus they are shown in three different possible locations. Before the triggering of LTP, some synapses may be functionally silent in that they contain no AMPA receptors in the synaptic plasma membrane. Nevertheless, the same expression mechanisms would apply.[85]

This activation of postsynaptic receptors results in a complex biochemical cascade inside the  postsynaptic neuron which results in an increase of the postsynaptic cell’s sensitivity to neurotransmitter, in large measure by increasing the activity of existing neurotransmitter receptors (Figure 23), and by increasing the number of receptors on the postsynaptic cell surface.[82] In the minutes, hours or days following the initial induction of LTP there is gene activation in the neuronal nucleus resulting in the synthesis and incorporation of new proteins into the neuronal membrane, the creation of new synapses,[84] alterations to the structure of the neuronal cell membranes, and changes in the number and/or distribution of neurotransmitter containing vesicles in the synapses. There is also remodeling of the pattern and of the character of synaptic connections between neurons. LTP may also involve the participation of the glial cells – supportive cells which surround neurons and which secrete neurotrophic factors responsible for maintaining neuronal health and viability.[86] There is also emerging evidence that changes in neuronal membrane lipid structure may be important to LTP; for instance it has recently been demonstrated that lipids can interact directly with glutamate transporters.[87]

The creation of indefinitely durable LTM is presumably an even more complex process, and involves not just the addition, subtraction, or modification of one type of synapse, but of many. In fact, there are at least 161different synapse morphologies, a few of which are shown in Figure 24 and 25, below.[18] These synapse morphologies and distributions undergo both transient and long-lasting changes during LTP and LTM.[88],[89]

Figure 24: Most synapses cover a small area and have a compact, roughly convex shape, such as numbers 51, 59, and 81, above. These are referred to as macular synapses. Larger synapses are often exhibit ‘holes’ in the middle. These holes are regions of cell membrane devoid of the specializations characteristic of the synapse, e.g. postsynaptic density, synaptic cleft, presynaptic active zone, etc. Synapses with holes, such as numbers 45, 46, 86, 90, 94, 96, and 100, are referred to as perforated synapses. Of the 161 synapses so far classified in the neuropil, 148 are macular, while the remaining 13 are perforated. The difference between macular and perforated synapses can be seen in electron micrographs in which the postsynaptic densities have been stained (Figure 25).[89]

Figure 25: Synapses in Hippocampal Area CA1 of the Rat: Scale: 1 micron. Most synapses in stratum radiatum (>90%) occur on dendritic spines. As shown in Figure 3, spines come in a variety of shapes. A thin spine (T) has a small head with a macular postsynaptic density. The length of the spine neck is much greater than its diameter. The mushroom spine (M) has a large head, typically greater than 0.6 microns in diameter. An elaboration of the endoplasmic reticulum, called a spine apparatus (sa) is often visible within the neck of a mushroom spine. Mushroom spines also tend to have perforated (perf) postsynaptic densities on the spine head. The stubby spine (S) does not have a constricted neck, and its overall length is roughly equal to its diameter. The stubby spine illustrated above possesses a macular postsynaptic density. Occasionally synapses occur directly on the shaft of a dendrite (shaft) without the participation of a dendritic spine. Symmetric (inhibitory) synapses in stratum radiatum tend to be shaft synapses. All of the symmetric synapses of the neuropil shown in Figure 23 are shaft synapses. [Sorra KE, Harris KM (1993) Occurrence and three-dimensional structure of multiple synapses between individual radiatum axons and their target pyramidal cells in hippocampal area CA1. J. Neurosci. 13:3736-3748. (5,414K PDF)]

Another feature observed in LTP is that while each dendritic spine in the hippocampus typically receives only one excitatory synapse on its head, sometimes these synaptic heads are segmented into multiple active zones. These “segmented synapses” have evoked much speculation regarding their possible role in synaptic plasticity.[88] Recent reports show that segmented synapses increase transiently after LTP induction in the hippocampus, then return to control levels within an hour.[84],[90] The complex morphology and multi-axonal interface of a typical segmented synapse of the hippocampus is shown in Figure 26, below. While not common, if segmented synapses are indeed lasting, and material to LTM, then the number of effective connections in the brain will have to be revised substantially upwards.

Figure 26: Reconstruction of ‘same-dendrite, multiple synapse boutons’ (sdMSBs) and related structures in a hippocampal brain slice. (a) The sdMSB makes a synapse with the head of one spine (x) on this section. Three of the axons (4,6,7) are visible between the spine head and the dendrite (Dend). (b) Three-dimensional reconstruction of the dendrite (gray), the sdMSB axon, and all seven axons (1–7) passing through the gap between the spines (x,y). Four of the axons (2,4,5,6) are cross-sectioned to avoid obscuring the other axons. Scale bar, 0.75 μm. [Fiala JC, Allwardt B, Harris KM. Dendritic spines do not split during hippocampal LTP or maturation. Nat Neurosci. 2002 Apr;5(4):297-8. PubMed PMID: 11896399.]

Understanding the Biophysical Consequences of Cryoinjury

As the foregoing discussion should make clear, the encoding of LTM likely relies upon a multiplicity of structural and biochemical changes, including the critical spatial relationship and apposition between dendrites, dendritic spines, neurons, and possibly even neuronal and glial cell membranes. It is within the context of this current understanding of the neurobiology of LTM that the effects of cryopreservation will now be considered.

Straight Freezing

Straight freezing is the cryopreservation of cells, tissues or organisms in the absence of added cryoprotection (in the form of colligative, or other cryophylactic molecules). Since most cells and organisms lack endogenous cryoprotection, the result is the conversion of almost all of the available water in the system into ice.

Figure 27: At left, above, is a light micrograph (400x) of the molecular layer[8] of the rabbit cerebral cortex subjected to freezing to -79oC in the absence of cryoprotection (straight freezing). The tissue is compressed between blocks of ice that have osmotically extracted the intracellular water. At right is the molecular layer of rabbit cerebral cortex tissue (10,000x) following thawing and fixation after straight freezing. The ultrastructure of the tissue resembles that of a tissue homogenate, rather than that of the molecular layer of the cerebral cortex.[91]

Undoubtedly the compressive forces are enormous under these conditions. What happens to the multiple species of brain cell membranes and their connections and embedded structures when they are dehydrated, biochemically destabilized, and then osmotically and mechanically compressed as a result of ice formation in straight freezing? Obviously, there will be shape changes in discrete membrane structures, but beyond that, to what extent will membranes merge, reorganize into novel structures, or otherwise become physically transformed in ways that would render inference of their pre-frozen state impossible – all of this occurring without thawing, and as a direct consequence of freezing? Definitive answers to these questions are not known, in part because the intense dehydration and compression of the tissue makes visualization of its ultrastructure virtually impossible in the frozen state.

In cryonics patients treated with straight freezing, these delicate and easily re-morphed structures will be crushed together and it might be impossible to tell, even with a complete 3-dimensional molecular level understanding of the remaining structure, what the original configuration was.  It may be that receptors, membrane proteins, and other uniquely configured membrane structures, like the micro-particles comprising the hypothetical image on a soap bubble, will be scattered in debris fields and intermingled with each other.

The character of the changes observed in thawed-fixed, straight frozen brain tissue, as seen in Figure 27, above, suggest that irreversible structural degradation has occurred during the freezing process (and is undoubtedly amplified during thawing). The tissue shows no evidence of plasma cell membranes, and most intracellular structures are no longer identifiable; with the exception of the nucleus and mitochondria – both of which show major morphological abnormalities. Compare the TEM of the molecular layer of the straight frozen—thawed rabbit cerebral cortex at right in Figure 27, above, with that of the molecular layer of the cerebral cortex of a control animal in Figure 28, below. These data provide little grounds for optimism about the conservation of the fine structures of the brain believed to be responsible for encoding LTM.

Figure 28: Control (perfusion fixed) TEM of the molecular layer of the rabbit cerebral cortex (10,000x ). [TEM by author]

Low to Moderate Molarity Cryoprotected Freezing

To the extent that colligative cryoprotectant replaces water in the brain, the effects seen in Figure 27 are attenuated. In the case of freezing in the presence of ~ 4 M glycerol, the fine structure of the tissue before, during, and after freezing can be directly imaged. The sequence of events and the ultrastructural sequelae of cryopreservation under those conditions are shown in Figure 29, A-C, below.

A: At left above is a rendering based upon the rotary shadow electron micrograph of a hippocampal neuron shown Figure 19. The neuron and the extracellular space have been equilibrated with 3.7 M glycerol, and freezing is beginning to take place as the neuron is progressively cooled to -79oC. The ice freezes out as pure water pushing an advancing front of hyperosmolar solution (purple) in front of it. At right is the condition of the tissue after glycerolization, but prior to the onset of freezing. [Artistic rendering and TEM by the author.]

B: At top left is an artistic rendering of the neuron and the surrounding extracellular medium in the frozen state at -79oC. The neuronal cell body, as well as the axon and dendrites are dehydrated and compressed between masses of ice. The interior of the neuron, as well as small islands in the interstices between ice masses, contains highly concentrated, vitreous glycerol-water-salt solution (purple). At right(and below) is a TEM of rabbit hippocampus (21,000x ) that was frozen in the presence of 3.7 M glycerol and fixed in the frozen state with osmium tetroxide using a technique known as freeze substitution.[92] [PMC free article] The neuropil is compressed between masses of ice and several tears in the tissue are evident (red arrows). [Artistic rendering by the author; TEM courtesy of Brian Wowk, Ph.D.]

C: At left is an artistic rendering of the nature and extent of worst-case cryoinjury to a hippocampal neuron following freezing and thawing in the presence of 3.7 M glycerol. The axon has been transected by ice, the cell membrane has been osmotically stressed to the point of lysis, and there are debris surrounding the cell, in the form of membrane and cytoplasmic contents, as well as detached dendrites and synapses. Some of the plasma membrane has reformed into blebs and vesicles. At right is a TEM (9,000x) from the hippocampus of rabbit cerebral cortex that has been frozen to -79oC, rewarmed, perfused with fixative and prepared for TEM. The nucleus of a large neuron is visible in the center of the upper third of the micrograph, however the plasma membrane appears fragmented and there are ice-induced cavities with debris present in a band that spans the lower, middle third of the image. [Artistic rendering and TEM by the author.]

Figure 29: A-C, above: Impact of cryopreservation (-79oC) and thawing on tissue from the CA-1 area of the hippocampus in the presence of 4 M glycerol.

 Figure 30: Appearance of feline cerebral cortex gray matter (medial temporal lobe) following freezing, thawing and fixation in the presence of 4 M glycerol (9000x). There is enhanced density of the ground substance (tissue texture) as a result of dehydration, and numerous small perforations of the neuropil that appear to be a result of ice formation. Overall, the fine structure appears well conserved and would seem to be inferable. [TEM by the author.]

Figure 31: Appearance of feline cerebral cortex gray matter (medial temporal lobe) following freezing, thawing and fixation in the presence of 4 M glycerol (15,000x). There is enhanced density of the ground substance as a result of dehydration, but very little evidence of injury as a result of ice formation. Overall, the fine structure appears well conserved and would seem to be inferable. [TEM by the author.]

High Molarity Cryoprotection Freezing


Figure 32: Artistic (left) rendering of a hippocampal neuron subjected to freezing to -79oC after equilibration with 7.5 M glycerol. Cell volume is conserved and ice formation is reduced to ~ 30% of the starting aqueous volume. At right is cerebral cortex tissue from the medial temporal lobe of a dog cryopreserved with 7.5 M glycerol, thawed, reperfused with fixative, and examined with transmission electron microscopy (15,000x). There is excellent conservation of the fine structure of the neuropil, and a notable absence of ice crystal artifacts, or debris. The capillaries (C) are intact and demonstrate uninterrupted adhesion of the endothelial cells to the basement membrane. The increased density of ground substance (tissue texture) and the presence of small spaces between ultrastructural elements are due to dehydration from the cryoprotectant agent (glycerol) and are reversible when the agent is removed. [Artistic rendering and TEM by the author.]

As the tissue cryoprotectant concentration approaches a vitrifiable amount (with concurrent suppression of ice formation) freezing damage is dramatically reduced. Not only is the volume of the system that is converted to ice greatly decreased, there is also a reduction in ice crystal size as result of the high cryoprotective agent (CPA) concentration. In the case of a CPA like glycerol, where the viscosity of the glycerol-water solution increases sharply, both as a function of increasing glycerol concentration and decreasing temperature, there is also a marked reduction in consolidation of smaller ice crystals into larger ones (recrystallization). The intracellular milieu becomes a glassy (vitreous) solid; in the case of systems cryoprotected with glycerol the glass transition point occurs at ~ -100oC.[93],

As can be seen in Figure 32 (above) and Figures 33 and 34 (below) the result of high molarity (glycerol) cryoprotection during freezing is dramatically improved conservation of tissue ultrastructure across anatomical locations and morphological levels. Synapses are intact with neurotransmitter vesicles exhibiting normal density and distribution. Cell membranes appear crisp and continuous, and there is no sign of blebbing or budding of vesicles from neuron, or other cell membranes.[91],[94]

Figure 33: A synapse in gray matter from the hippocampus at 40,200x magnification. The presynaptic junction contains small packets of neurotransmitter (A) visible as granules. Note the overall crisp appearance of both the synaptic membranes and adjacent structures of the neuropil. This degree of preservation at the synaptic level was uniformly observed in all samples examined. [TEM by the author.[91]]

Figure 34: White matter from the corpus collosum at 6700x magnification. Note the excellent preservation of the capillary (A) and its endothelial cell plasma membranes. The nucleus (B) shows typical loss or reorganization of nucleoplasm; this is seen more frequently in frozen-thawed brains than in brains just perfused with glycerol and fixed without freezing. Several axons (C) exhibit typical shrinkage of axoplasm and alteration in myelin structure. The increase in free space between axons and other structures is the result of glycerol-induced dehydration. [TEM by the author.[91]]


Laboratory Experience

The only structural studies of vitrified mammalian brains which are known to exist are those conducted by, or under the auspices of 21st Century Medicine (21CM), a cryobiological research and development company located in Fontana, CA. The most definitive data so far disclosed employed M-22, a vitrification solution developed by 21CM, primarily for renal vitrification.[95]The composition of M-22 is shown Figure 35, below. This complex mixture of colligative and actively ice inhibiting cryoprotectants exhibits comparatively low toxicity, even at concentrations of ~60%. A unique feature of M-22 is the presence of two synthetic molecules that inhibit ice growth by binding to both the  a and c axes of ice.[96],[97],[98] These molecules stabilize the solution against ice nucleation and propagation, allowing for use of the much slower cooling and rewarming rates needed for ice free cryopreservation of large tissues masses, such as humans organs.

Figure 35: Twenty First Century Medicine’s M-22 vitrification solution contains 5 penetrating colligative cryoprotective agents as well as 6% of non-penetrating polymers – two of which are highly active ice-blocking molecules; Supercool X-1000 and Supercool Z-1000. X-1000 contains 80% of the syndiotactic stereochemical form of polyvinyl alcohol and 20% vinyl acetate and Z-1000 is a linear polymer of polyglcerol with an average molecular weight of 750 Da. Both bind to the a and c axes of ice crystals, stabilizing solutions they are present in against ice formation during slow rates of cooling and rewarming.[95][Image is courtesy of Brian Wowk, Ph.D., of 21st Century Medicine, Inc., http://www.21cm.com/]

As a result of very recent advances in vitrification technology, it is now possible to vitrify entire mammalian organs.[99] However, two significant remaining problems are to inhibit ice growth  during rewarming (“devitrification”) in some tissues that do not equilibrate well with the cryoprotectant chemicals, and to overcome the problem of fracturing, which occurs during cooling to or below Tg.

Ice formation occurs during rewarming as a result of the generation of ultramicroscopic ice nuclei during cooling, which cannot grow or propagate, because there is too little energy in the system and too little time for ice to grow as a result of steady and continued cooling to Tg. While devitrification is a significant hurdle to be overcome, it is a technological, rather than a theoretical one. Additionally, virtually all research on reversible vitrification of organs has been conducted on the kidney, and this presents a unique challenge, because the interior of the organ, the renal medulla, is very poorly circulated (Figure 36). It is thus difficult to load a sufficient concentration of cryoprotectants into this poorly vascularized tissue to completely avoid ice formation.[99]


Figure 36: Visual appearance of ice in a rabbit kidney that was cross-sectioned during rewarming. The kidney was perfused with a cryoprotective mixture called M22 at -22°C, cut in half, immersed in M22, vitrified at -135°C, and eventually re-warmed at ~1°C/min while being periodically photographed. Times (1:30 and 1:40) represent times in hours and minutes fom the start of slow warming. The temperatures refer to ambient atmospheric temperatures near the kidney but not within the kidney itself. The upper panel shows the kidney at the point of maximum ice cross-sectional area, and the lower panel shows the kidney after complete ice melting. Both panels show the site of an inner medullary biopsy taken for differential scanning calorimetery in order to determine the actual concentration of cryoprotectants in the tissue with high precision. [http://cryoeuro.eu:8080/download/attachments/425990/FahyPhysicBiolAspectsRenalVitri2010.pdf?version=1&modificationDate=1285892563927]

A fair summary of the current technological state of the art is that under ideal (laboratory) conditions, it is likely now possible to place complex mammalian organs, such as the rabbit kidney, into indefinitely long suspended animation with little or no loss of viability, and no damage as a consequence of structural disruption due to ice formation. The use of radio frequency, or microwave illumination to speed rewarming, the use of warm gas (such as helium) to perfuse the organ’s circulation, or a combination of these modalities, may offer a workable solution to the problem of ice formation during rewarming. Perhaps most impressively, one mammalian kidney has survived vitrification and rewarming sufficiently intact to permit immediate support of the rabbit from which it was removed (as the sole kidney), until the animal was sacrificed for evaluation 29 days after the organ was re-implanted.[99]

Figure 37: The first kidney to survive vitrification shortly before it was removed from the animal for evaluation after supporting its life as the sole kidney for 29 days. [Image is courtesy of Brian Wowk, Ph.D., of 21st Century Medicine, Inc, http://www.21cm.com/]

An additional complicating factor in achieving reversible (viable) vitrification of the mammalian brain has been the inability to continue cryoprotectant perfusion at the same subzero temperatures (-20oC) that have proven essential for recovery of rabbit kidneys following loading and unloading with M-22. As can be seen in Figure 38, below, perfusion of the terminal concentration of M-22 is not possible below ~ -3-4oC. Exposure to ~8.2M M-22 at such a relatively high temperature, for the final ~60 min of perfusion required to load the brain with the CPA mixture results in major loss of viability, but does not visibly affect brain ultrastructure, as imaged using TEM.

Figure 38: Cryoprotection and cooling protocol used to achieve structural vitrification of the rabbit brain at 21st Century Medicine, Inc., CPA loading commences at a temperature of ~+4oC and continues at that temperature for ~ 60 minutes while the M-22 concentration is gradually increased to ~4 M. The temperature is then reduced to ~ -3oC while the CPA concentration is increased to ~ 8M. The total time required to achieve full equilibration of the brain with M-22 is ~ 180 minutes, after which the organ is immediately transferred to an air-blast cooler for very rapid cooling to ~ -135oC. [Image is courtesy of Brian Wowk, Ph.D., of 21st Century Medicine, Inc., http://www.21cm.com/]

The ultrastructure of brains cryopreserved using the 21CM vitrification technique shows no evidence of ice formation. As previously noted, there is extensive dehydration of all imaged areas of the brain, with associated increase in ground substance density which makes assessment of very fine structures difficult. Reassuringly, it is possible to not only viably recover brain slices from this state, but to demonstrate the persistence of pre-vitrification induction of LTP in such vitrified and recovered brain slices.

Figure 39: TEM of rabbit cerebral cortex gray matter (~ 15,000x) subjected to vitrification, rewarming and perfusion fixation using M-22 and the perfusion protocol shown in Figure 38, above. The extensive dehydration induced by cryoprotective loading makes it difficult to visualize the finer elements of the ultrastructure such as vesicles and microtubules. The overall appearance of tissue in terms of the larger structural elements and their relationship to each other is apparently normal. [Image is courtesy of Brian Wowk, Ph.D., of 21st Century Medicine, Inc., http://www.21cm.com/]

Figure 40: High magnification TEM (~ 40,000x) of vitrified rabbit brain tissue discloses the presence of difficult to visualize fine structures – in this case a synapse (S) with synaptic vesicles visible as dark densities in the synaptic bouton and a small myleinated (M) axon containing condensed axoplasm (A). Importantly, the topographical and structural relation of the synapse to the surrounding structures appears intact. [Image is courtesy of Brian Wowk, Ph.D., of 21st Century Medicine, Inc., http://www.21cm.com/]

Figure 41: TEM of rabbit cerebral cortex white matter (15,000x) subjected to vitrification, rewarming and perfusion fixation using M-22 and the perfusion protocol shown in Figure 38, above. There is severe dehydration of the axoplasm and separation between some of the layers of myelin. There is no evidence of ice formation, and all structural changes appear to be a consequence of CPA-induced dehydration. These changes are reversible with controlled removal of CPA and return of the tissue to incubating medium (see Figure 42, below). [Image is courtesy of Brian Wowk, Ph.D., of 21st Century Medicine, Inc., http://www.21cm.com/]


Figure 42: Mosaic of TEM’s demonstrating continuity of a long axon (red arrows) in a rabbit brain subjected to vitrification, rewarming and perfusion fixation using M-22 and the perfusion protocol shown in Figure 39, above. The tear in the tissue (green arrow) is believed to be a processing artifact. Two capillaries visible near the middle and top of the mosaic (blue arrows). [Image is courtesy of Brian Wowk, Ph.D., of 21st Century Medicine, Inc., http://www.21cm.com/]

Figure 43: Hippocampal CA4 cells following recovery from vitrification using a fully reversible, viability conserving technique. Following rewarming and unloading of the CPA the tissue was incubated in artificial cerebrospinal fluid at 35oC for >60 min before being fixed in low-osmolality Karnovsky’s and examined by TEM.[100]

Both freezing and vitrification have the potential to disrupt the structures that encode LTM in ways that would leave them uninferrable. Vitrification may do this by the expedient of altering membrane structure irreversibly by dehydration, or by changing the molecular structure of the membranes (or membrane components) by directly perturbing their structure. Vitrification solution is not water, and water is critical to the structure of many of the molecules inside cells. Indeed, a good part of the science behind designing tolerable vitrification solutions is to make them behave as much like water as possible – while at the same time behaving as good, or good enough, glass forming agents when cooled.[49] On a purely structural basis it would seem that vitrification, applied under ideal (laboratory) conditions, is preserving the structures that encode memory and personality. To the extent that structural vitrification (as opposed to fully reversible, viable vitrification) perturbs or damages the biochemistry associated with LTP, there are grounds for concern. However, it seems unlikely that such injury would render the biochemistry of the brain uninferable, and therefore nonviable by the information-theoretic criterion for death.[22]

Real World Considerations

While laboratory investigations conducted under ideally controlled conditions provide considerable reassurance that existing cryopreservation techniques can conserve the essential structural and biochemical elements that comprise personal identity, such techniques are rarely available to human cryonics patients. Due to medico-legal and logistical constraints, most patients presenting for cryopreservation suffer extensive peri- and post-cardiac arrest global ischemia. When cryoprotection is delivered under these conditions in the laboratory setting, the results are very discouraging.

Figure 44: Feline cerebral cortex frozen, thawed and fixed in the presence of 4 M glycerol after 30 minutes of normothermic ischemia, followed by 24 hours of cold ischemia at ~2-4oC. There was severe disruption of the tissue fine structure by ice (A,B), in addition to changes associated with ischemia such as mitochondrial swelling and blebbing of the endothelial cells (A). [TEMs by the author.[101]

In 1983 studies were undertaken to determine the effects of 30 minutes of normothermic ischemia followed by 24 hours of cold ischemia at ~ 2-4oC.[101] Healthy adult cats were anesthetized; heparinized and cardiac arrest was induced. The animals were allowed to remain undisturbed on the operating table for 30 minutes, and then were packed completely in water ice, where they were allowed to remain for 24 hours. They were then perfused to 4 M glycerol using a linear increase in glycerol concentration during the ~ 60 minute perfusion interval. Following cryoprotective perfusion, the animals were cooled to dry ice temperature at ~ 3oC/hour, and to liquid nitrogen temperature at ~4oC/hour. Due to the unexpected presence of fracturing in the brain and other viscera, fixative reperfusion following thawing was not possible, and brain tissue samples for TEM were fixed by immersion.

As can be seen in Figure 44, above, there was extensive freezing damage superimposed over ischemic injury to the tissue. The mitochondria were swollen and often showed little internal structure. Neuronal plasma membranes were impossible to identify and the neuropil was macerated by what appeared to be ice artifacts. Large peri-capillary ice holes were almost uniformly present and large islands of tissue had the appearance of a tissue homogenate, as was observed in animals subjected to straight freezing.

The Problem of Ischemia and Ischemia-Reperfusion Injury

Hypoperfusion Following Reperfusion

Figure 45: The no reflow phenomenon as documented by Ames, et al., in the rabbit brain in 1968. The control brain on the left was perfused with a colloidal carbon solution while the animal was still alive and under anesthesia. At right, the brain of an animal reperfused with carbon solution after 15 minutes of global normothermic cerebral ischemia – an interval of ischemia all too common in human cryopreservation patients. The pale white areas are zones of no-reflow or failed reperfusion, and account for 93% of the surface area in this cortical slice, despite use of hypertensive reperfusion at 120 mm Hg.[104]

In cryonics patients, a significant contributor to reperfusion injury is hypoperfusion after the artificial restoration of circulation using closed chest cardiopulmonary support (CPS). Not only is CPS very inefficient at restoring adequate perfusion, blood flow to the brain, in particular, is impeded as a consequence of the cerebral “no-reflow” (CNR) phenomenon.[102] The no-reflow phenomenon was first described by Ames and Fisher in 1968,[103],[104] and was observed in the brains of animals subjected to reperfusion after experimentally induced global cerebral ischemia (GCI) from cardiac arrest lasting for periods of 5 minutes or longer. Interestingly, no-reflow does not usually develop in the heart, or other organs and tissues, until they have experienced periods of ≥ 30 min of normothermic global ischemia. Ames, et al., originally proposed three mechanisms as the cause of CNR; 1) glial and endothelial cell edema causing a reduction of the capillary lumen diameter to below the critical threshold for the passage of RBCs, 2) hyperviscosity of micro-vessel blood due to concentration of plasma proteins and formed blood elements as water is relocated from the microvascular space to intracellular space under the influence of the Gibbs-Donan Equilibrium in ischemia, and  3) alterations in the neurovascular endothelial surface as a result of bleb formation due to endothelial cell edema (See Figure 46).

Figure 46: The no reflow phenomenon, first demonstrated by Ames and Fisher in 1968, constitutes a major barrier to successful cerebral resuscitation. Beginning at ~5 minutes after the start of normothermic global cerebral ischemia (GCI) a variety of biomechanical changes can be observed at the microscopic and especially at the ultramicroscopic level. Due to the failure of ion pumping cellular edema becomes pronounced at this point, resulting in swelling of both the brain parenchymal and capillary endothelial cells. This edema decreases capillary diameter to considerably less than that of the red blood cells (RBCs), leading to RBC plugging of the vessels. The cellular response to edema is to shed small vesicles of cell membrane material, apparently in an attempt to regulate cell volume and prevent hypervolemic cell lysis. These vesicles or “blebs” may interfere with the flow of the formed elements of the blood, and when they occur between the endothelium and the sarcolemma of the pre-capillary sphincters, they may also act to decrease capillary diameter resulting in reduced or absent blood flow.

Additionally, there are rheological changes in the blood itself. As water translocates from the blood in the capillary lumen, plasma proteins and formed blood elements become concentrated and hyper-viscous, and consequently resistant to flow. The surfaces of the RBCs are prevented from sticking to each other due the existence of a charge barrier, the zeta potential, which is pH sensitive. Under conditions of acidosis, as pertain in ischemia, the zeta potential collapses and the RBCs become sticky and aggregate into masses which cannot pass through the micro-vessels. The RBCs themselves also undergo changes, most notably becoming rigid as a result of intracellular ATP depletion .This reduces RBC deformability, making their passage through brain capillaries difficult or impossible.

Finally, there is growing evidence that prolonged period of GCI cause activation of immune/inflammatory cascade resulting in neutrophil adhesion and activation, platelet aggregation and activation of the clotting cascade, the latter resulting in the possible formation of micro-thrombi in the small vessels, particularly in the brain venules.

Since the initial work by Ames, et al., it is has become apparent that the pathophysiology of CNR is considerably more complex. Other factors that have been identified as causative are changes in the character of the endothelial surface during ischemia, which make it stickier due to increases Nuclear factor kB (NFkB) and Tumor Necrosis Factor-α  (TNF-α), resulting in elevated levels of a wide range of other pro-adhesion and pro-inflammatory chemokines.[105],[106] Additionally, the generation of free radicals, in particular peroxynitrite and the hydroxyl radical, degrade the extracellular matrix and the capillary basal lamina, resulting in increased permeability of the BBB with consequent development of interstitial cerebral edema.[107] Both free radical and leukocyte activity can also degrade the endothelial cell tight junctions to the point that frank extravasation of formed blood elements occurs, along with activation of the clotting cascade, resulting in the formation of fibrin lactoids and frank clots in the capillary lumen.[108] Free radical and leukocyte activation can also result in complete destruction of cells in the neurovascular endothelium, resulting in patches of exposed basement membrane, which in turn result in micro-thrombus formation. Blebs, debris from lyzed RBCs and endothelial cells, aggregated platelets, and precipitated macromolecules can also accumulate to form capillary occluding masses of debris (Figure 46).

The diameter of the average RBC is ~7.7μ, about 1μ larger than the diameter of the average brain capillary. In order for RBCs to pass through capillaries it is necessary for them to deform (and in so doing place the maximum amount of surface area in contact with the vascular endothelium to facilitate gas exchange). RBC deformability is critically dependent upon RBC intracellular adenosine triphosphate (ATP) concentration being adequate. With periods of ischemia of ~ 7 minutes, RBCs become depleted of ATP and become rigid, making passage through brain capillaries more difficult (higher arterial pressure required) or impossible.[109]

Dispersed RBCs Aggregated RBCs

Figure 47: The zeta potential is the degree of negative charge on the surface of the RBC; the potential difference between the negative charges on the RBC and the cations in the fluid portion of the blood which constitutes of zone of charge the cells that prevents them from adhering to each other (above left). Changes in the cation content, or reduction of the pH of the plasma can collapse the zone of repulsive charge around the RBCs,  allowing them to agglomerate and stick together in clumps.

The surface of RBC (and most cell) membranes is intrinsically sticky, and what keeps them from adhering to each other and aggregating into a solid mass is a complex interaction between sialic acid groups (sialoglycoprotein) on the RBC membrane, which give the cell a negative charge, and positive ions in plasma that are attracted to the negatively charged RBC membrane.[110] This zone of oppositely charged ions surrounding the RBC surface is called the “fixed layer.” Outside the fixed layer, there are varying compositions of ions of opposite polarities, forming a cloud-like zone. This area is called the “diffuse double layer,” and the whole of the diffuse double zone is electrically neutral. Thus, the net positive charge surrounding the RBCs keeps them apart due to electrostatic repulsion. The electrostatic potential of this zone, measured at the plane of hydrodynamic slippage outside the surface of the cell, is called the zeta potential.[111] Zeta potential is considered to be the electric potential of this inner area, including this conceptual “sliding surface” (Figure 48). As this electric potential approaches zero, particles tend to aggregate. Put more succinctly, the zeta potential is the degree of negative charge on the surface of the RBC, the potential difference between the negative charges on the RBC and the cations in the fluid portion of the blood.

Figure 48: Graphic illustration of the zeta potential surrounding the RBC. The zeta potential consists of 3 layers of charge; the negative charge of the RBC membrane, a boundary layer of positively charged cations that travel with the cell as it moves through the blood plasma, and an outer layer of positive charge that is more dynamic composed of varying compositions of ions of opposite polarities, forming a cloud-like area that exists at the boundary of shear, or the “slipping phase” at the plane of hydrodynamic slippage outside the RBC. These last two layers are known as the “diffusible double layer.”

A critical determinant of the zeta potential is pH. The zeta potential of RBCs is optimized around a pH of 7.4. Under conditions of acidosis, and in particular where the pH drops below 6.6, as is the case in ischemia, the zeta potential of the RBC collapses and the intrinsic stickiness of the membrane surface is unmasked.[112] RBCs in contact with each other will tend to stick, and in the absence of flow (which acts as a dispersing agent) and under the influence of gravity, RBCs begin to aggregate and sediment out of the plasma.[113] Where RBCs are in contact with capillary endothelium, they will tend to stick, and the force required to dislodge them will be far larger than under physiological conditions. The aggregation of RBCs under acidic conditions was, at one time, used as an alternative method to centrifugation for removing RBCs from solution during washout of cryoprotectant following freezing, using a technique known as cytoagglomeration.[114]

Even in the absence of ischemia, dynamic variations in flow, pH and plasma chemistry can increase the amount of time RBCs in flowing blood spend in contact with each other. The longer the contact times between RBCs, the greater the viscosity of the blood. Increased blood viscosity, and the presence of loosely bound clumps or aggregates of RBCs, result in a blood sludging; a condition of greatly slowed and irregular flow in the micro-vessels (arterioles, capillaries and venules).[115]

Figure 49: Aggregation or agglomeration of RBCs into irregular clumps is the most common pattern of RBC adhesion seen in both RCIRI and GCIRI. The impact on flow is devastating resulting in either severe blood sludging or complete arrest of microcirculatory flow.

Within 60 seconds of the start of  ischemia, pH in the cerebral micro-vessels quickly drops to ~6.8, and then declines to ~6.2 after only 5 minutes or more of GCI.[116]Sedimentation of RBCs, WBCs and platelets becomes pronounced after 6 minutes and is difficult to reverse due to the adhesion of the cells to each other.[117] The acidemia of prolonged ischemia may also adversely affect the configuration of some plasma proteins causing them to act as bridging molecules between the RBCs thus further increasing agglomeration.

Figure 50: The adhesion of RBCs to each other in a “stack of coins” configuration, known as rouleaux is the less prevalent, but still common pattern of RBC aggregation observed during and after both RCIRI and GCIRI. As is the case with irregular aggregation of RBCs rouleaux formation has a profound negative impact on perfusion.

When flow is re-established, higher pressures and higher flow rates will be needed to generate the shear required to re-suspend sedimented blood cells, and to disrupt agglomerations of cells in the microvasculature.[118] With the passage of enough time (~30 min), agglomeration and sedimentation extend to the large vessels, where much larger masses of adherent cells will form, fall under the influence of gravity, and consolidate. This macro-scale hyper-viscous sludge will be very difficult to disrupt, and can be expected to compromise flow for prolonged periods of time following the start of reperfusion.

The work of Hossman, et al.,[119] and Sterz, et al.,[120] has demonstrated the critical importance of providing adequate circulatory support following global cerebral ischemia.  Loss of autonomic regulation, depressed myocardial function secondary to ischemic insult of the myocardium, and autonomic dysfunction all serve to depress MAP and cerebral perfusion following restoration of circulation. Both Hossman’s and Sterz’s work has demonstrated significant improvements in neurological outcome if circulation is immediately supported extracorporeally during reperfusion – an option which is not available to cryonics patients.

In-house research conducted by the author has demonstrated that the cerebral microcirculation remains profoundly compromised for 30-60 minutes following reperfusion, even when circulation is restored using cardiopulmonary bypass. Brain parencymal and endothelial cell swelling, as well as changes in the zeta potential of the red blood cells, may all be contributing to the extensive blood sludging and microvascular stasis observed after reperfusion following 10 minutes of global normothermic ischemia in the laboratory.

Figure 51: Canine cerebral cortical (gray matter) capillary plugged with a mass of red cells following extensive washing (5 L) with a colloid containing hyperosmotic solution, followed by fixation perfusion with Karnofsky’s fixative. [TEM by the Author.]

As the electron micrograph above demonstrates, even following attempts at reperfusion with a hyperosmotic physiological solution at a MAP of 90 mmHg, there are many instances of capillaries plugged with aggregated red cells, as seen above.

Figure 52: At left, baseline pial circulation in the dog brain prior to induction of cardiac arrest and the 15 minute ischemic insult. At right, flow is seen to be sluggish with obvious sludging in the larger vessels, and complete stasis observed in many of the smaller ones ~30 minutes after the onset of reperfusion. [Intravital microscopy by Jerry Leaf and the author.]

The microcirculation in the pia remains disturbed and sluggish even 30 minutes after reperfusion following 15 minutes of normothermic GCI as can be seen in Figure 51 which shows baseline flow in pial vessels and flow 30 minutes after ROSC at a MAP of 80 mmHg.

Consequences of Ischemia-Induced Derangement of the Microcirculation for the Human Cryopreservation Patient

In the case of human cryopreservation patients, it is apparent that the warm and cold ischemia suffered by many has effects on the brain (and somatic tissues) that combine features of GCIRI, RCIRI and Multisystem Organ Failure (MSOF, or the post-resuscitation syndrome). Injury associated with the post-resuscitation syndrome does not develop under normal clinical conditions until 12 to 24 hours after the ischemic insult. Leukocyte activation is “slow” (hours) and compromise to the BBB is typically delayed until 12 to 24 hours after reperfusion.[121]

Figure 53: In the terminally ill patient suffering from progressive degenerative disease, the immune-inflammatory cascade is already activated. In cancer patients, NFkB and TNF-α will often be expressed and are responsible for the cachexia of the wasting syndrome. In some cancers (lung, prostate, colon), elements of the clotting cascade may be activated, and the patient will be in a hypercoagulable state weeks or months prior to cardiac arrest.

Activation of the Immune-Inflammatory Cascade

In the human cryopreservation patient a number of factors appear to be responsible for the acceleration of the inflammatory and tissue destroying components of reperfusion injury, causing them to manifest during the period of initial stabilization following cardiac arrest and the pronouncement of legal death (and especially by the time cryoprotective perfusion is initiated if there has been a prolonged period of cold ischemia; i.e., transport packed in ice absent perfusion and gas exchange). The first of these is the terminal illness, and any satellite pathologies that preceded, or were a consequence of it (Figure 53). As an example, a patient experiencing terminal decline from metastatic adenocarcinoma will inevitably experience up-regulation of a host of pro-inflammatory cytokines.[122],[123] With some cancers there will be chronic, low level activation of the clotting cascade as a direct result of the tumor’s biochemistry, and it should be noted that 50% of all cancer patients show evidence of deep vein thrombosis, or other kinds of intravascular clotting at autopsy.[124],[125]

Such patients will almost invariably experience ongoing localized ischemia as tumor compresses and compromises blood flow to healthy tissues; and there will also be ongoing necrosis in the center of the poorly vascularized tumor masses with attendant release of pro-inflammatory tissue breakdown products. Chronic and acute pain also up-regulate the immune-inflammatory cascade. Many medications used to treat the disease or its complications will adversely affect blood rheology leading to blood sludging and additional incomplete regional ischemia. Most neoplasms provoke enormous and sustained release of TNF-α which will have adverse effects on capillary integrity and blood coagulation. Finally, chemotherapy and radiation therapy both have dramatic pro-inflammatory systemic effects, as do the intercurrent infections that are so often complications of these treatments. Malnutrition with protein catabolism and cell death is yet another likely inflammation inducing factor.

Figure 54: A prominent feature of moderate to severe ischemic injury in the absence of prompt blood washout and extracorporeal support in the cryonics patient is red trapping in the tissues. At left are photos taken of the arterial pump raceway and arterial filter at the conclusion of cryoprotective perfusion (4.5M glycerol). The circuit (L) of the patient given prompt CPS, followed by blood washout and continuous ECMO support until the start of CPA perfusion, shows only trace amounts of RBCs and has an unreadable hematocrit. The circuit shown (R) was from a patient who experienced sudden cardiac arrest, was given heparin and a brief interval of CPS in the hospital ED, and was then transported packed in ice with CPA perfusion starting ~20 hours later.

As a result of these destructive processes, the terminally ill patient is not only primed to experience the destructive effects of ischemia on the vascular endothelium, they have, in fact, often begun to experience many of the pathophysiological mechanisms of ischemia-reperfusion injury weeks, or even months before cardiac arrest occurs.

With the immune–inflammatory cascade already significantly activated, the peri-arrest period of severe regional ischemia (as tumor mass critically encroaches on vital organ structure and function) coupled with what are often very long (6-48 hours) peri-arrest intervals of severe hypoxic and ischemic injury during the agonal period, there is full-scale activation of the immune-inflammatory cascade. The result of this is that the patient is primed for reperfusion injury, and in fact may be experiencing reperfusion-type injury on both a regional and a systemic basis prior to cardiac arrest.

Pre-Cardiac Arrest Regional and Global Cerebral Ischemia?

Many patients dying slowly will experience the clinical signs of failed cerebral perfusion (fixed, unresponsive pupils, absence of corneal and deep tendon reflexes) anywhere from 30 minutes, to an hour or more prior to cardiac arrest. This typically occurs during a period of profound bradycardia (20-30 bpm) accompanied by 3-4 agonal breaths per minute, or erratic and infrequent agonal breaths (1-2 minute)[126] In some patients this condition may persist for many hours. In such cases there is clinical evidence at autopsy of the body (neuropatients) of systemic mixed regional and global ischemic injury, as indicated by the presence of clots in the femoral veins, pulmonary inflammation/edema, erosion of the gastric mucosa, and areas of focal necrosis in the liver, kidneys, and ileum, as determined by light microscopy.[127],[126] Rarely, onset of rigor has been observed in the gastrocnemius, peroneus longus and peroneus brevis muscles of the lower limbs an hour or more prior to cardiac arrest.[126]

Patients experiencing this kind of injury respond to CPA perfusion by developing severe peripheral and visceral edema, sometimes accompanied by transudation of large volumes of perfusate from the lungs (ET tube) and leakage of similarly large volumes of perfusate into the upper and lower gut, resulting in abdominal distension, and in some cases, compartment syndrome. Such patients invariably experience red cell trapping in the tissues which persists throughout cryoprotective perfusion.[128],[129],[130],[131],[132],[133] This is especially remarkable given the large volume of solution passed through the patient’s vasculature (120 L), the hyperosmolality of the CPA solution, and the relative cellular impermeability of a number of the cryoprotectants (i.e., glycerol, ethylene glycol). Patients with very short warm ischemic times (<8 minutes) who receive prompt and effective CPS, followed by blood washout and/or extracorporeal support, do not exhibit red cell trapping, and do not typically develop CPA perfusion limiting cerebral edema.[128],[129],[130],[131],[132],[133]


Figure 55: Patients with minimal peri-arrest ischemic injury who are given prompt and effective CPS followed by blood washout and either immediate CPA perfusion, or extended (~8-10 hours) ECMO support respond to CPA perfusion with massive cerebral dehydration (above right) and relatively uniform CPA perfusion of the skin. The patient shown below has a few infarcted areas evident on the bridge of the nose, probably secondary to pressure from ice bags, and is already evidencing cerebral cortical retraction from the dura, even during the first 30 minutes of CPA perfusion (7.5 M glycerol).

Cerebral Edema

Figure 56: The burr hole of a human cryopreservation patient who experienced a brief period of CPS with heparinization, followed by packing in ice, and transport to the CPA perfusion facility. One hour into CPA perfusion, the brain abuts the burr hole opening, and a steady stream of aggregated RBCs can be seen exiting the burr hole in the perfusate leaking from the torn bridging veins between the dura and pia matters. The bridging veins tore as a consequence of the brief interval of cerebral dehydration which accompanied the initiation of CPA perfusion.

Compromise of the BBB, as indicated by the development of cerebral edema, may range from moderate to severe, and is often the reason for discontinuation of CPA perfusion.239, 240 In patients who are stabilized immediately post-arrest under good conditions, and who respond well to CPS (adequate EtCO2, SpO2, MAP) the BBB remains intact as evidenced by massive (~50%) shrinkage of the brain during CPA perfusion.[134],[135] Patients who have experienced high quality transport in the presence of minimal peri-arrest injury, but who are subsequently transported by air without continuous asanguineous cardiopulmonary bypass support, also suffer damage to the BBB, as evidenced by failure of brain to shrink (and/or remain shrunken) during CPA perfusion. In such patients there is often initial shrinkage of the brain in response to CPA loading, followed by return to isovolemia, or the development of a slight degree of cerebral edema by the end of CPA perfusion.[136],[137]

Figure 57: The impact circulatory obstruction on cryoprotectant equilibration in a cryonics patient who underwent ~24 hours of cold ischemia is evident in the inhomogeneous glycerolization of the skin at the conclusion of CPA perfusion. False color imaging discloses a patchwork of well, poorly, and completely unglycerolized areas of the patient’s skin. This pattern of patchy, compromised, or failed perfusion is present in the brain, as well as in the skin.

Cryonics patients who experience significant ischemic insult, be it peri- or post-cardiac arrest, warm or cold, will, as a consequence, suffer from multifocal areas of cerebral infarction and severely reduced flow on both the micro- and the macro-level. This will result in failed or inadequate cryoprotection of the brain, with many micro- and macro-domains of tissue undergoing straight freezing, or freezing in the absence of adequate cryoprotection. Patients who have suffered sufficiently long periods of warm and/or cold ischemia will be un-perfusable, and will of necessity be straight frozen. Given our current understanding of the biophysical basis of LTM, and in particular of “declarative” or “biographical” memory,” [138],[139],[140][9] it would appear that this critical element of personal identity is unlikely to survive cryopreservation under conditions of straight freezing, or in circumstances where the level of cryoprotection is very low, or very inhomogeneous, with substantial areas of the brain being subjected to neuronal membrane re-morphing, and severe topographical and spatial distortions of the neuropil as a result of ice formation and the attendant biochemical, osmotic, and mechanical stresses.


The prospects for the conservation of personal identity via cryopreservation under optimum conditions, particularly with the use of no, or very low ice forming methods, such as high molarity cryoprotective freezing or vitrification, seem excellent. TEM studies in animals demonstrate good preservation of both the gross and ultrafine structure of the neuropil, as well as of the white matter of the cerebral cortex. Synaptic connectivity and attachment to dendrites and dendritic spines appears undisturbed by these preservation methods, and where ice formation does cause injury, the structure appears to be displaced, rather than crushed or re-morphed – and as such, should allow inference of its undamaged, pre-cryopreservation state. The demonstration of the persistence of LTP following vitrification of mammalian hippocampal brain slices provides considerable grounds for optimism that the biochemical basis for encoding memory is also being conserved; at least in the case of vitrification under ideal conditions.

The criticality of avoiding both warm and cold ischemia cannot be overemphasized. The consequences of un-cryoprotected, or inadequately cryoprotected freezing are dire. There is nearly uniform loss of neuronal membrane structure, maceration of the neuropil, and obvious re-morphing of cell membrane components. These kinds of changes, especially if they are occurring during freezing, as well as during thawing, are not compatible with the survival of the patient using the information-theoretic criterion for determining death. Cryonicists may wish to rethink the way they communicate the viability of cryonics to the public – as well as how they conduct their personal lives – if they realistically hope to benefit from cryopreservation as a potentially reversible method of medical time travel.


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117.     Nemoto E, Frank, S.: Brain tissue pH after global brain ischemia and barbiturate loading in rats. Stroke 1981, 12:77-82.

118.     Mchedlishvili G, Gobejishvili, L, Beritashvili, N.: Effect of intensified red blood cell aggregability on arterial pressure and mesenteric microcirculation. Microvasc Res 1993, 45:233-242.

119.     Hossmann K: Reperfusion of the brain after global ischemia: hemodynamic disturbances. Shock 1997, 8(2):95-101; discussion p. 102-103.

120.     Sterz F, et al.: Multifocal cerebral blood flow by Xe-CT and global cerebral metabolism after prolonged cardiac arrest in dogs. Reperfusion with open-chest CPR or cardiopulmonary bypass. Resuscitation 1992, 24(1):27-47.

121.     Mossakowski M, Lossinsky, AS, Pluta, R, Wisniewski, HM.: Abnormalities of the blood-brain barrier in global cerebral ischemia in rats due to experimental cardiac arrest. . Acta Neurochir Suppl (Wien) 1994, 60:274-276.

122.     Martinet N, Charles, T., Vaillant, P, et al.: Characterization of a tumor necrosis factor-alpha inhibitor activity in cancer patients. Am J Respir Cell Mol Biol 1992, 6:510-515.

123.     Ueda T, Shimada, E, Urakawa, T.: Serum levels of cytokines in patients with colorectal cancer: possible involvement of interleukin-6 and interleukin-8 in hematogenous metastasis. J Gastroenterol 1994, 29:423-429.

124.     Green K, Silverstein, RL.: Hypercoagulability in cancer. Hematol Oncol Clin North Am 1996 10(2):499-530.

125.     Rickles F, Levine, M, Edwards, RL.: Hemostatic alterations in cancer patients. Cancer and Metastasis Reviews, 11(3-4):237-248.

126.     Darwin M: Unpublished case report of Alcor Life Extension Foundation patient Eugene Theodore Donovan, A-1169, 21 March, 1989. 1989.

127.     Darwin M: Cryopreservation case report: Jerome Butler White. posted to CryoNet on 09 Jul 1994 03:02:55 EDT http://wwwcryonetorg/cgi-bin/dspcgi?msg=2868, see also: http://wwwcryonetorg/cgi-bin/dspcgi?msg=2867 and http://wwwcryonetorg/cgi-bin/dspcgi?msg=2874 1994.

128.     Darwin M: Unpublished case report of Alcor Life Extension Foundation patient A-1133, August, 1987. 1987.

129.     Leaf J, Federowicz, M, Hixon, H.: Case report: two consecutive suspensions, a comparative study in experimental human suspended animation. Cryonics 1985, 6(11):13-38.

130.     Darwin M: The cryonic suspension of A-1184: http://www.alcor.org/cryonics/cryonics9208.txt. . Cryonics 1992, 13(8):9-11.

131.     Henson K: Unpublished case data of Alcor patient A-1475, Stanislaw Penksa, 26 November, 1995. 1995.

132.     Darwin M, Leaf, JD, Hixon, H.: Case report: neuropreservation of Alcor patient A-1068: http://www.alcor.org/cryonics/cryonics8504.txt. Cryonics 1986, 7(2):17-32.

133.     Darwin M: Jerry Leaf enters cryonic suspension: http://www.alcor.org/cryonics/cryonics9109.txt Cryonics 1991, 12(9):19-25.

134.     Darwin M: Cryopreservation case report: Arlene Francis Fried, A-1049: http://www.alcor.org/Library/html/fried.html. In.: Alcor Life Extension Foundation; 1995.

135.     Darwin M: Cryopreservation of James Gallagher, CryoCare patient #C-2150: http://www.alcor.org/Library/html/casereportC2150.htm. In.: Alcor Life Extension Foundation; 1995.

136.     Darwin M: Unpublished case report of Alcor Life Extension Foundation patient A-1410, 27 July, 1992. 1992.

137.     Bridge S: The cryonic suspension of Alice Black. Cryonics 1988, 9(11):15-25.

138.     Tulving E: Episodic and semantic memory. In: Organization of Memory. Edited by E Tulving WD. New York: New York: Academic Press; 1972: 381–403.

139.     Gabrieli J, Kao, Y.: Development of the Declarative Memory System in the Human Brain. Nature Neuroscience 2007, 10:1198-1205.

140.     Eichenbaum H: A cortical-hippocampal system for declarative memory. . Nature Reviews Neuroscience 2000, 1:41-50.

Selected Bibliography of Full Text PDFs

Brain Ultrastructure and LTP:

Harris KM (1980) Relationships between dendrite and spine neck diameters in freeze-fractured rat hippocampal formation. Biol. Bull. 159:470-471. (646K PDF)

Harris KM, Landis DM (1986) Membrane structure at synaptic junctions in area CA1 of the rat hippocampus. Neurosci. 19:857-872. (3,253K PDF)

Harris KM, Stevens JK (1989) Dendritic spines of CA1 pyramidal cells in the rat hippocampus: serial electron microscopy with reference to their biophysical characteristics. J. Neurosci. 9:2982-2997. (7,143K PDF)

Chicurel ME, Harris KM (1992) Three-dimensional analysis of the structure and composition of CA3 branched dendritic spines and theirsynaptic relationships with mossy fiber boutons in the rat hippocampus.J. Comp. Neurol. 325:169-182. (6,353K PDF)

Sorra KE, Harris KM (1993) Occurrence and three-dimensional structure of multiple synapses between individual radiatum axons and theirtarget pyramidal cells in hippocampal area CA1. J. Neurosci. 13:3736-3748. (5,414K PDF)

Harris KM, Sultan P (1995) Variation in number, location, and size of synaptic vesicles provides an anatomical basis for the non-uniformprobability of release at hippocampal CA1 synapses. J.Neuropharmacology34:1387-1395.   (851K PDF)

Spacek J, Harris KM (1997) Three-dimensional organization of smooth endoplasmic reticulum in hippocampal CA1 dendrites and dendriticspines of the immature and mature rat. J. Neurosci. 17:190-203.  (2,560K PDF)

Spacek J, Harris KM (1998) Three-dimensional organization of cell adhesion junctions at synapses and dendritic spines in area CA1of the rat hippocampus. J. Comp. Neurol. 393:58-68.  (947K PDF)

Shepherd GMG, Harris KM (1998) Three-dimensional structure and composition of CA3–>CA1 axons in rat hippocampal slices: implicationsfor presynaptic connectivity and compartmentalization. J. Neurosci. 18:8300-8310. (964K PDF)

Sorra KE, Fiala JC, Harris KM (1998) Critical assessment of the involvement of perforations, spinules, and spine branching in hippocampalsynapse formation. J. Comp. Neurol. 398:225-240.  (1,643K PDF)

Ventura R, Harris KM (1999) Three-dimensional relationships between hippocampal synapses and astrocytes. J. Neuroscience 19(16):6897-6906. (888K PDF)

Cooney JR, Hurlburt JL, Selig DK, Harris KM, Fiala JC (2002) Endosomal compartments serve multiple hippocampal dendritic spines from a widespread rather than a local store of recycling membrane. J. Neurosci 22:2215-2224. (763K PDF)

Harris KM, Cruce WLR, Greenough WT, Teyler TJ (1980) A Golgi impregnation technique for thin brain slices maintained in vitro. J. Neurosci. Methods.2:363-371. (3,633K PDF)

Sorra KE, Harris KM (1998) Stability in synapse number andsize at 2 hr after long-term potentiation in hippocampal area CA1. J. Neurosci.18:658-671. (1,407K PDF)

Kirov SA, Sorra KE, Harris KM (1999) Slices have more synapses than perfusion-fixed hippocampus from both young and mature rats. J Neurosci. 19(8):2876-2886.  (1,426K PDF)

Ventura R, Harris KM (1999) Three-dimensional relationships between hippocampal synapses and astrocytes. J. Neurosci. 19(16):6897-6906. (888K PDF)

Sorra KE, Harris KM (1998) Stability in synapse number and size at 2 hr after long-term potentiation in hippocampal area CA1. J. Neurosci.18:658-671. (1,407K PDF)

Sorra KE, Fiala JC, Harris KM (1998) Critical assessment of the involvement of perforations, spinules, and spine branching in hippocampalsynapse formation. J. Comp. Neurol. 398:225-240 (1,643K PDF)

Kirov SA, Sorra KE, Harris KM (1999) Slices have more synapses than perfusion-fixed hippocampus from both young and mature rats. J Neuroscience 19(8):2876-2886.  (1,426K PDF)

Kirov SA, Harris KM (1999) Dendrites are more spiny on mature hippocampal neurons when synapses are inactivated. Nature Neuroscience 2(10):878-883. (643K PDF)

Cooney JR, Hurlburt JL, Selig DK, Harris KM, Fiala JC (2002) Endosomal compartments serve multiple hippocampal dendritic spines from a widespread rather than a local store of recycling membrane.  J. Neurosci. 22:2215-2224. (763K PDF)

Fiala JC, Allwardt B, Harris KM (2002) Dendritic spines do not split during hippocampus LTP or maturation. Nat. Neurosci. 5:297-298. (311K PDF)

Ostroff LE, Fiala JC, Allwardt B, Harris KM (2002) Polyribosomes redistribute from dendritic shafts into spines with enlarged synapses during LTP in developing rat hippocampal slices. Neuron 35:535-545. (552K PDF)

This website is a superb resource for visual information as well as full text papers on the fine structure of the mammalian central nervous system:





Fahy, GM, Wowk, B, et al. Cryopreservation of organs by vitrification: perspectives and recent advances. Cryobiology 48 (2004) 157–178: http://www.21cm.com/pdfs/cryopreservation_advances.pdf

Fahy, GM, Wowk, B, Wu, J. Cryopreservation of Complex Systems: The Missing Link in the Regenerative Medicine Supply Chain. Rejuvenation Research. 2004, 9(2):279-91: http://www.21cm.com/articles/Missing_Link.pdf

Fahy G, Wowk, B, Pagotan, R, et al.: Physical and biological aspects of renal vitrification. Organogenesis 2009, 5(3):167-175: http://cryoeuro.eu:8080/download/attachments/425990/FahyPhysicBiolAspectsRenalVitri2010.pdf?version=1&modificationDate=1285892563927

Wowk B: Anomalous high activity of a subfraction of polyvinyl alcohol ice blocker. Cryobiology 2005, 50(3):325-331: http://www.21cm.com/pdfs/anomalous.pdf

Pichugin Y, Fahy, GM, Morin, R.: Cryopreservation of rat hippocampal slices by vitrification. Cryobiology 2006, 52(2):228-240: http://www.21cm.com/pdfs/hippo_published.pdf

Brain Cryopreservation by Freezing:

Darwin, M, Russell, S, Wakfer, P, Wood, L, Wood, C, Effect of a human cryopreservation protocol on the ultrastructure of the canine brain. (Originally published by BioPreservation, Inc., as BPI Tech Brief 16 on CryoNet and sci.cryonics, May 31, 1995): http://www.alcor.org/Library/html/braincryopreservation2.html and http://www.alcor.org/Library/html/braincryopreservation1.html.

Darwin M, Leaf, JD.: Cryoprotective perfusion and freezing of the ischemic and nonischemic cat: http://www.cryonet.org/cgi-bin/dsp.cgi?msg=1389, http://www.cryonet.org/cgi-bin/dsp.cgi?msg=1390, http://www.cryonet.org/cgi-bin/dsp.cgi?msg=1391, http://www.cryonet.org/cgi-bin/dsp.cgi?msg=1392  See also: Federowicz,  MG. and Leaf JD. Cryonics. issue 30, p.14,1983.

Suda, I., Kito, K, Adachi, C. Viability of Long Term Frozen Cat Brain in Vitro. Nature. v. 212, Oct. 15, p. 167:1966: http://cryoeuro.eu:8080/download/attachments/425990/SudaNature1966.pdf.

Suda, I., Kito, K, Adachi, C. Bioelectric discharges of isolated cat brain after revival from years of frozen storage. Brain Res.  70;527-531:1974: http://www.ncbi.nlm.nih.gov/pubmed/5970120?dopt=Abstract.   Retrieved 2010-08-31

[1]The resolution of direct digital imaging technology using charge-coupled devices (CCDs) is still well below that pf the best fine grain photographic films – color or black and white.

[2] For instance, does a person remain the ‘same’ person after head injury that causes major and permanent changes in personality or in cognitive ability? Or, alternatively, does a person ‘survive’ brain injury that leaves his personality and cognitive capabilities intact, but which deprives the individual of some or all of his memories? If permanent amnesia does occur, will the loss of some memories prove identity critical, whilst the loss of others be merely inconvenient, but not represent a fundamental compromise to personal identity?

[3] Exposure to environmental toxins such as mercury or to psychoactive drugs may also permanently alter cognition and personality in adults.

[4] By interacting with water so strongly via hydrogen bonding CPAs may also make the remaining water less biological available to perform the solventing and stabilizing functions it normally provides.

[5] Biologists arguably ‘know better’ in that they presumably have a better grasp of the fluid nature of cell and cell component morphology.

[6] Ischemia is absent or inadequate blood flow to tissues as occurs in cardiac arrest, heart attack and stroke.

[7] Rather, such a configuration is a product of conscious design at the meta-level.

[8] The outer lamina of the cerebral cortex, containing the neuronal soma and dendrites of Purkinje cells, the axons of the granule cells, and the cell bodies, dendrites, and axons of basket cells.

[9] Declarative memory (sometimes referred to as explicit memory) is one of two types of long term human memory. It refers to memories which can be consciously recalled such as facts and events.[1]  Its counterpart is known as non-declarative or Procedural memory, which refers to unconscious memories such as skills (e.g. learning to ride a bicycle). Declarative memory can be divided into two categories: episodic memory which stores specific personal experiences and semantic memory which stores factual information.

Posted in Cryobiology, Cryonics Philosophy, Cryonics Technology (General), Ischemia-Reperfusion Injury | 16 Comments

The Pathophysiology of Ischemic Injury: Impact on the Human Cryopreservation Patient, Part 4

By Mike Darwin

Intracellular Acidosis & Alkalosis

While clearly not the sole, or even the major source of injury in ischemia, intracellular lactic acidosis does contribute to the pathophysiology of ischemia,173 Cortical lactate levels above a threshold of 18 – 25 μM/g result directly in irreversible neuronal injury.174, 175

Decrease in pH as a consequence of lactic acidosis has also been shown to directly injure and inactivate mitochondria. Lactic acid consumption of NADH (which is needed for ATP synthesis) may also interfere with adequate recovery of ATP levels post ischemically.176 Lactic acidosis also increases iron decompartmentalization, increasing the amount of free-radical mediated injury.177

Paradoxically, rapid normalization of intracellular pH (pHi) following ischemia results in severe injury as a result of at least two mechanisms: rapid and complete opening of the (PT) pore and the generation of greatly increased quantities of free radicals (the “pH paradox”). Because the (PT) port cannot open under conditions of acidosis, acidosis is protective. Normalization of pHi before repletion of cellular ATP is associated with regional lysis of the capillary endothelial cells, leaving highly thrombogenic exposed basal lamina, and generating debris that contributes to non-thrombotic micro-vessel plugging.

The pH paradox present a problem, in that in order to restore metabolic homeostasis and to achieve adequate hemodynamic recovery, it is necessary to at least partially correct the profound extracellular acidosis that develops after 10-30 minutes of GCI. One particularly attractive solution to this problem is to use drugs which function to block the Na++/H antiporter, also called the Na+–H+ exchange mechanism (NHE), a plasma membrane exchange glycoprotein transporter that functions in intracellular pH regulation, cell volume regulation.

The NHE mechanism is inactive under normal conditions,178 but becomes the primary dynamic cellular buffering system during ischemia; extruding protons for sodium in an electro-neutral exchange. The ATP-dependent sodium–potassium exchanger that normally extrudes sodium to prevent calcium overload is impaired or rendered non-functional by prolonged ischemia and reperfusion. However, the ATP independent Na+–Ca2+ exchanger remains active in reducing cellular sodium accumulation, so that subsequent calcium overload develops through its reversed activity. Cellular edema due to sodium overload, results in narrowing of the capillary lumen from swollen endothelial and parenchymal cells that impairs blood flow and contributes to the leakage of excitatory amino acids.179-181

In 1991 Murphy, et al.,182 discovered that the antiarrhythmic drug amiloride inhibits the NHE in myocardial ischemia and it was subsequently determined that more lipid soluble analogs of amiloride were even more effective in doing so.183,184 Of particular significance is the recent finding that n-methyl isobutyl amiloride is profoundly effective in protecting against GCIRI in the brain by virtue of its strong activity in inhibiting the NHE antiporter and its ability to rapidly cross the BBB. This makes methyl isobutyl amiloride a particularly attractive molecule to achieve inhibition of the NHE and delay normalization of neuronal pHi during reperfusion after cardiac arrest.185

Neutrophil Activation

Since the late 1960s, polymorphonuclear leukocytes (PMNLs) and monocytes & macrophages have been implicated as significant causes of pathology in cerebral ischemia. During the last decade there has been a veritable explosion of research documenting the role of PMNLs in reperfusion injury. Most of the initial work done in this area focused on PMNL-mediated reperfusion injury to the myocardium, establishing that PMNL activation and subsequent plugging and degranulation (resulting in release of oxidizing compounds) is responsible for the no-reflow phenomenon following myocardial ischemia.186-189 In particular, the work of Engler has demonstrated that PMNL activation is responsible for plugging at least 27% of myocardial capillaries and is further responsible for the development of edema and arrhythmias upon reperfusion.190

Figure 20: Cascade of signaling molecule activation  involved in PMNL adhesion to the vascular endothelium.


Figure 21: The Pathophysiology of Cerebral Ischemic Injury. The above text and figure are reproduced with some changes from Safar, P., and Bircher, N.G., Cardiopulmonary Cerebral Resuscitation. 1988; W.B. Saunders Company, Ltd., London, UK. pp. 236-37. Schematic summary of the hypothesized mechanics of tissue injury in cerebral ischemia during both the circulatory arrest (left) and reperfusion (right) intervals.  During normal conditions intracellular calcium (Ca++) levels are maintained at approximately 100 nM.  Ca++ regulation is achieved by the plasma membrane Ca/Mg-ATPase and the ATP dependent uptake of Ca++ into the endoplasmic reticulum (ER) and mitochondria.  The release of bound Ca++ from the ER store is believed to be triggered by inositol-1,4,5 triphosphate (IP3) and/or by free arachidonic acid (AA).  Release of Ca++ bound in the mitochondria is not thought to occur until the ER stores are depleted.  The initial response of many different cell types to stimulation–i.e., ligand-receptor interaction, hormone receptor binding, chemotactic peptide binding to polymorphonuclear leukocytes, or presynaptic or post-synaptic neurotransmitter binding , in an increase in Ca++ due to release of intracellular ER-bound Ca++, an influx of extracellular Ca++, or both.  Changes in many intracellular enzyme activities, including phospholipases and protein kinases, the polymerization of g-actin to f-actin, and that of tubulin to microtubules, all occur at different “set points” of Ca++.  Therefore much of the control of intracellular processes is related to the level of Ca++. During ischemia (left), in all cells (including neurons) the level of ATP decreases rapidly to near zero.  This causes an increase in free calcium, even without an increase in IP3.  The addition of 2-deoxyglucose to cells, which acts as an ATP sink, causes a rapid increase in Ca++.  Increases in Ca++ activate phospholipase A2, which breaks down membrane phospholipids (PL) into free fatty acids (FFA), particularly AA.  The AA causes increased activity of the cyclooxygenase pathway to produce prostaglandins (PG), including thromboxane (TX) A2, the lipoxygenase pathway to produce leukotrienes (LT), or both.  Furthermore, during ischemia the hydrolysis of ATP via AMP leads to accumulation of hypoxanthine (HX).  Increased Ca++ enhances the conversion of xanthine dehydrogenase (XD) to xanthine oxidase (XO), priming the neuron for the production of the oxygen free radical O2- intracellularly, once O2 is reintroduced.  During reoxygenation (right), significantly increased levels of at least three free radical species (in oblique boxes) that result in direct and indirect damage to cell membranes and the extracellular matrix (and thus lead to edema and microcirculatory failure) may be formed: O2-, OH•, and free lipid radicals (FLR).  O2- may be formed from two sources: 1) the previously described XO system and 2) activation of neutrophils in the microvasculature due to increased LT production by the neurons or simply by absent blood flow and consequent margination and diapedesis of neutrophils from the microvasculature.  Increased O2- production leads to increased H2O2 production as a result of the intracellular action of SOD. H2O2 is controlled by intracellular catalase.  Increased O2- production leads to increased OH•, due to the Fenton reaction (Fe++ +H2O2—>Fe+++.+OH+OH•) with iron liberated from ferritin, and the Haber-Weiss reaction (O2-+H2O2—>OH-+ OH•).. Each or all of these oxidants can result in lipid peroxidation and the production of LFRs.  All free radicals can cause leaky membranes and currently irreversible cell damage.  Furthermore, reoxygenation restores ATP via oxidative phosphorylation, which may result in massive uptake of Ca++ into mitochondria.  Thus, increased Ca++ as a result of ischemia and reoxygenation, by itself, and by triggering free radical reactions, may well be the principal cause of neuronal necrosis during reperfusion.

To what extent leukocyte plugging occurs in the brain following global cerebral ischemia remains controversial.191 Anderson, et al., have examined the question of how rapidly leukocyte plugging occurs following cerebral ischemia using a bilateral carotid artery plus hypotension model in the dog. They noted no leukocyte plugging after 3 hours of reperfusion following a 40-minute ischemic episode.192 In the case of human cryopreservation patients, leukocyte plugging is likely to be of greater significance in facilitating GCIRI due to the mixed nature (global and regional) of the ischemic insult. It is certainly the case that neutrophils are a major mediator of acute ischemic injury in a variety of extra-cerebral organ systems and it seems likely that their activation is responsible for many of the effects of ischemia observed in the brains of human cryopreservation patients, including the loss of capillary integrity and the degradation of spinal cord endothelial ultrastructure seen as a result of prolonged CPS during Transport.193

When PMNLs are activated they generate large amounts of hydrogen peroxide. A large fraction of the hydrogen peroxide, aided by myeloperoxide (also released by activated PMNLs), reacts with the halides Cl-, Br-, or I- to produce their corresponding hypohalous acids (HOX).194 Because the concentration of Cl- is more than a thousand times greater than the other halides, the hydrogen peroxide-myeloperoxidase system generates Cl- , most often in the form of HOCl-.  HOCl- (used as household bleach) is capable of damaging a wide range of organic molecules including most of those that make up the structure of the cells and the proteinaceous extracellular matrix.195 As Klebanoff, et al., have pointed out, the amount of HOCl- generated by the neutrophil is impressive: 106 neutrophils can generate 2 x 107 mol of HOCl- – enough to destroy 150 million E. Coli in a matter of milliseconds.196

The direct destructive effects of HOCl-are probably limited in vivo by a variety of mechanisms.197 Most probably, the hypohalous acids act to inflict the lion’s share of injury by interacting with PMNL collagenase, elastase, gelatinase, and other proteinases. As is shown in Figure 1-22 it is now believed that the oxidants released from the neutrophil create a halo of oxidized alpha-1-proteinase inhibitor that allows released elastase (and probably others of the 20 or so known neutrophil-secreted proteolytic enzymes)198 to begin degrading the extracellular matrix, thus destroying capillary integrity and interfering with tissue metabolism and anabolism.

Figure 22: Interactions between Neutrophil Elastase, α1- Proteinase Inhibitor (α1-PI), and Chlorinated Oxidants (green). The left half of the cartoon shows neutrophil oxidants creating a zone of oxidized α1-proteinase inhibitor that allows released elastase to attack and degrade endothelial cells and adjoining tissue. Because α1-proteinase inhibitor can inhibit elastase only inefficiently, free enzyme may also be detected. The right half of the cartoon shows an alternative setting in which only a small portion of the α1-proteinase inhibitor is oxidized, thus ensuring the efficient regulation of the released elastase. In either setting proteolysis can occur to a limited degree subadjacent to the neutrophil. In the inset: E=elastase, I=Inhibitor and ox=oxidized. (Adapted from Weiss, SJ. The role of PMNL in mediating ischemic injury: Tissue destruction by neutrophils. N Engl J Med. 1989. 320: p. 365-76.).

In RCIRI, it is clear that neutrophil activation with accompanying release of HOCl- and activation of elastase is a key factor in initiating the systemic cascade of the immune-inflammatory response which terminates in delayed multisystem organ failure (MSOF).199 The extent to which this pathway is a factor in acute global cerebral ischemic injury by causing acute injury and hypoperfusion immediately after the insult is not yet clear, but likely depends upon the adequacy of reperfusion and the quality of intensive care (since hyperpyrexia, episodes of hypotension, and inadequate post ROSC MAP all likely activate PMNLs).

End of Part 5


173) Siesjo, B., Cell damage in the brain: a speculative synthesis. J Cereb Blood Flow Metab. 1981. 1: p. 155-85.

174) Rhenchrona, S., Effect of different degrees of ischemia and tissue lactic acidosis on the short-term recovery of neurophysiologic and metabolic variables. Exp Neurol. 1985. 87: p. 458-73.

175) Kalimo, H, Rehncrona, S, Soderfeldt, B., The role of lactic acidosis in the ischemic nerve cell injury. Acta Neuropathol Suppl. 1981. 7: p. 20-2.

176) Lowry, O., The stability of pyridine nucleotides. J Bio Chem, 1961. 236: p. 2756-59.

177) Siesjo, B., Influence of lipid peroxidation in vitro. J Cereb Blood Flow Metab. 1985. 5: p. 253-58.

178) Hartmann, M, Decking, UK., Blocking Na+-H+exchange by cariporide reduces Na_ overload in ischemia and is cardioprotective. J Mol Cell Cardiol. 1999. 31(11): p. 1985–95.

179) Kristian, T, Siesjö, BK., Calcium in ischemic cell death. Stroke. 1998. 29: p. 705–18.

180) Kristian, T, Kuroda, S, Siesjö, BK., Mechanisms of ischemic brain damage: the mitochondrial hypothesis revisited. In: Robertson JK, Nowak TS Jr., eds. Frontiers in CerebrovascularDisease: Mechanisms, Diagnosis and Treatment. Armonk, NY: Futura Publishing Company, Inc, 1997. p. 261–73.

181) Tymianski, M, Charlton, MP, Carlen, PL, Tator, CH., Source specificity of early calcium neurotoxicity in cultured embryonic spinal neurons. J Neurosci. 1993;13: p. 2085–104.

182) Murphy, M, Perlman, RE, London, C, Steenbergen, E., Amiloride delays the ischemia-induced rise in cytosolic free calcium.Circ. Res. 1991. 68: p. 1250-1258.

183) Karmazyn, M., Na+/H+ exchange inhibitors reverse lactate-induced depression in postischaemic ventricular recovery. Br. J. Pharmacol. (1993), 108. p. 50-56.

184) Moffat, MP, Karmazyn, M., Protective effects of the potent Na/H exchange inhibitor methylisobutyl amiloride against post-ischemic contractile dysfunction in rat and guinea-pig hearts. J Mol Cell Cardiol. 1993. 25(8): p. 959-71.

185) Ferimer, HN; Kutina, KL; LaManna, JC., Methyl isobutyl amiloride delays normalization of brain intracellular pH after cardiac arrest in rats. Critical Care Medicine. 1995. 23(6) p. 1106-1111

186) Valli, M., Influence of excitatory amino acids on the outcome of cerebral ischemia. Presse Med. 1987. 16(23): p. 1118-21.

187) Engler, R., Role of leukocytes in response to acute myocardial ischemia and reflow in dogs. Am J Physiol. 1986. 251: p. H314-322.

188) Engler, R., Consequences of activation and adenosine mediated inhibition of granulocytes during myocardial ischemia. Federation Proc. 1987. 46(2407-12).

189) Beck, J., et al., Leukocyte-endothelium interactions in global cerebral ischemia. Acta Neurochir Suppl. 1997. 70: p. 53-5.

190) Engler, R., Consequences of activation and adenosine mediated inhibition of granulocytes during myocardial ischemia. Federation Proc. 1987. 46(2407-12).

191) Hartl, R., et al., Experimental antileukocyte interventions in cerebral ischemia. J Cereb Blood Flow Metab. 1996. 16(6): p. 1108-19.

192) Anderson, M., Experimental brain ischemia: Assessment of injury by magnetic resonance spectroscopy and histology. Neurol Res. 1990. 12: p. 195-204.

193) Halliwell, B., Oxygen Radicals and Tissue Injury: Proceedings of a BrookLodge Symposium. Augusta, MI 27-29 April, 1987. Federation of American Societies for Experimental Biology and Medicine, Bethesda, MD  1988, 1987: p. 1-143.

194) Klebanoff, S., Products of Oxygen Metabolism. In: Inflammation: Basic Principles and Clinical Correlates, eds. Gallin, IJ , Goldstein, IM and Snyderman, R, 1988. New York, Raven Press, 1988: p. 391-444.

195) Test, S.T., et al., Generation of nitrogen-chlorine oxidants by human phagocytes. J Clin Invest. 1984. 74(4): p. 1341-9.

196) Test, ST Weiss,  SJ., Quantitative and temporal characterization of the extracellular H2O2 pool generated by human neutrophils. J Biol Chem. 1984. 259(1): p. 399-405.

197) Weiss, SJ., Tissue destruction by neutrophils [see comments]. N Engl J Med. 1989. 320(6): p. 365-76.

198) Henson, P., Phagocytic Cells: Degranulation and Secretion. In: Inflammation: Basic Principles and Clinical Correlates, eds. Gallin, IJ , Goldstein, IM and Snyderman, R. Vol. New York, Raven Press, 1988. 1988. 363-380.

199) Broner, CW, et al., Effect of scavengers of oxygen-derived free radicals on mortality in endotoxin-challenged mice. Crit Care Med, 1988. 16(9): p. 848-51.

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Achieving Truly Universal Health Care

By Mike Darwin

Contemporary Medicine: Playing Peek-a-Boo with Death

The Proper End of Medicine

In my experience, physicians get evaluations that parallel those most often given to prostitutes; they don’t pay enough attention to you, there is typically a lack of the desired amount of enthusiasm and intimacy, the critical emotional moments are faked, the encounter never lasts long enough, you may discover as a consequence of your visit that you have a loathsome disease, the hourly rate is punishing, and  the most you can hope for is palliation, not real relief.

The first thing that anyone needs to understand about medicine is what its proper goal is. That’s actually pretty simple: to cure disease and maintain good health. No further qualifications are necessary. Once that proposition is accepted, it then should become obvious that the end goal, and the ultimate ideal of medicine, is to keep people alive and in good health indefinitely. Even the television physician pundits, like Dr. Oz, and CNN’s Sanjay Gupta, can sense that this is coming, and in fact, Sanjay pretty much said so:

“Practical immortality may now be within our grasp thanks to the cutting-edge scientific research and amazing medical breakthroughs that are coming at such astonishing speed we can hardly keep up. “1

- Sanjay Gupta, M.D.

Figure 1: Immortality is a lot like sex, in that it is something few will admit to wanting a lot of, and that almost everyone thinks their neighbor has too much of.

So, despite the fact that most people, when asked, will recoil in horror from the notion of personal, biological immortality, the fact is that that is exactly what they expect, exactly what they want, and exactly what they will effectively demand. Unfortunately, most of the medicine we practice today is not only not going to provide immortality any time soon, it is going to bankrupt us while turning us into human fleshpots, sitting in the solariums of nursing homes and extended care facilities the world over.

The late great physician-philosopher-writer Lewis Thomas, first identified the problem in 1974, in his classic book, The Lives of a Cell. Thomas wrote insightfully about three different kinds of medicine we humans are capable of practicing, classifying them as Prevention, No Technology, Low Technology, Halfway Technology and High Technology. I have created a color wheel of Thomas’ medical technologies, and added one of my own: Futile Technology – the kind of technology which increasingly characterizes the medicine we practice today (Figure 2).

Figure 2: The Spectrum of current medical technologies practiced today

Prevention and low technology medicine are fairly straightforward concepts and do not need our attention here. But High Technology Medicine (HTM), Futile Technology (FT), and especially Halfway Technology (HT), deserve considerably greater scrutiny.

Figure 3: The distribution of heal care expenditures over a lifetime: most of the money is spent on the last decade of life and most of that on futile and ineffective medicine that turns dying into a long, costly, morbid process. Nation-states would do better to advise their citizens to smoke and drink with abandon if they are truly interested in reducing the amount of suffering, and avoiding bankrupting their entire economies. Alternatively…

Thomas elegantly describes Halfway Technology as follows:

“Halfway technology represents the kinds of things that must be done after the fact, in efforts to compensate for the incapacitating effects of certain diseases whose course one is unable to do very much about. By its nature, it is at the same time highly sophisticated and profoundly primitive… It is characteristic of this kind of technology that it costs an enormous amount of money and requires a continuing expansion of hospital facilities… It is when physicians are bogged down by their incomplete technologies, by the innumerable things they are obliged to do in medicine, when they lack a clear understanding of disease mechanisms, that the deficiencies of the health-care system are most conspicuous… The only thing that can move medicine away from this level of technology is new information, and the only imaginable source of this information is research. The real high technology of medicine comes as the result of a genuine understanding of disease mechanisms and when it becomes available, it is relatively inexpensive, relatively simple, and relatively easy to deliver.” —Lewis Thomas2

Figure 4: Polio victims on Iron Lung support in a school gymnasium in the mid-1950s.

To understand the difference between HT and High Technology medicine (HTM), Thomas used the paradigm of the Polio epidemics of the mid-20th century as an example.3 Today, very few people understand either what the Polio epidemics of the 1950s were like, or the divergent ways that both researchers and clinicians sought to address the scourge. On the one hand, hundreds of thousands of people were contracting polio, with many suffering irreversible bulbar paralysis; which meant that they were unable to breathe. They were conscious and very much alive, but they were unable to use their respiratory muscles to ventilate themselves.

Figure 5: Jonas Salk, discoverer of the first clinically deployed Polio vaccine.

For many of such paralyzed patients, a relatively new medical device in the form of the Iron Lung represented an opportunity to go on living. In some patients the paralysis retreated, or vigorous physical therapy allowed them to recover sufficiently that they could once again breathe on their own.4 But for many, the Iron Lung was a life sentence of paralyzed immobility inside a cylindrical ‘steel coffin’ as seen in Figure 4.

A minority of scientists at that time believed that it might be possible to defeat Polio by the expedient of a vaccine,5 and so an intense competition for funds began between those who sought to secure more Iron Lungs to support the ever growing legion of patients with respiratory paralysis, and those who sought to understand the fundamental basis of the disease (in the context of their technological era) and treat it by eliminating it.6 In other words, these researchers wanted to get to the root cause of the illness and stop it there, rather than to develop every more sophisticated Iron Lungs, and other prostheses, to pinch-hit for the muscles rendered useless and atrophied by Polio.

In one of the most rapid translation of bench research to bedside application, Jonas Salk and his colleagues developed a workable Polio vaccine7 which was rolled out for public use in 1955 – the year I was born – just in time to ensure that yours truly would not end up in an Iron Lung, or be ‘lucky’ enough to escape a brush with Polio confined to wheelchair, or using walking braces with a case of ‘simple paralysis,’ as did US President Franklin Delano Roosevelt. HT is Iron Lungs, and the Salk, and later Sabin vaccines, were HTM. Insulin treatment for diabetes, artificial hearts/ left ventricular assist devices, total hip and knee replacements, and drugs for hypertension are also all halfway medicine. They treat the clinical manifestations of disease with varying degrees of efficiency and cost effectiveness, but they do not ever affect a cure.

Figure 6: The chart above shows the approximate current distribution of health care dollars by the type of medical technology.

Most people aren’t satisfied with medicine because, fundamentally, most of medicine is still unable to address the underlying causes of disease. Medicine used to be almost completely worthless from a scientific standpoint, and physicians were mostly about diagnosis, prognosis, and hand-holding. Since 1900, medicine has been able to treat a few illnesses definitively, but it is still mostly about indirect, and halfway treatments that are costly, and in no way definitive. The older the patient, the more this will be the case, because the real cause of most disease in the developed world is aging. Cancer is aging, hypertension is aging, diabetes is aging, most of urology (including sexual dysfunction) is aging, stroke is aging, Alzheimer’s is aging, and 3/4ths of every health care dollar is currently spent on the deterioration and chronic illnesses that are a product of aging.

Patient’s don’t have the experience of their physicians examining them, and then saying, “Well, you see, the problem is right here in alpha-N-1-letterbox beta gene. I’ve re-coded that gene, as well added on the 5.01 Rejuvenation and Cell Repair Package. Within 10 days to two weeks, you should have the libido of a 14-year-old, the appearance of a 20-year-old, the stamina of an endurance runner, and the life span of a Sequoia redwood.” Doctors can only very indirectly manipulate the machinery that makes us run, and they usually have to use costly and chronically applied chemicals that are typically as poisonous as they are therapeutic. Nobody is truly going to be thrilled about doctors until they can really cure illnesses.

Figure 7: This is as good as it gets. If contemporary medicine reached it goal of ‘squaring the curve,’ and extending the average life span to at or near the maximum lifespan (~ 120 years), this is how you can expect to end up. The photo at left is of ‘Supercentenarian’ Marie Bremont, taken on her 115th birthday in 2001. Absent definitive regenerative medicine, all that contemporary medical technology can do is to maintain the function of existing tissues, until the point where physiological reserves become so depleted, that the slightest environmental challenge causes death.

Because medicine is mostly a halfway business, it will have a terrible bite-back effect that will ultimately render it unsustainable, and/or leave the patient population truly pissed-off. The better we get at halfway medicine, the less cost effective it is. Dialysis, total artificial hearts, Gleevec, Viagra, anti-hypertensives, artificial joints, all these things ultimately create more and more people whose survival, let alone their restoration to health or full function, will eventually cost more than they, or the society as a whole, could possibly pay for, even with a  with a lifetime of hard work. In fact, right now medical care is consuming 16% of the US GDP, and that will rise to over 20% in just 4 years! No economy that we have any experience with can tolerate that kind of cash drain – it is simply unsustainable. And what’s worse, a quick glance at Figure 6 shows that currently we are spending ~25% of our health care dollars on FT – medicine which does no good, and which usually causes  harm, by inflicting further suffering, and damaging the ability of the system to deliver care to patients who can genuinely benefit.

Figure 8: US healthcare costs projected to 2015 as a percentage of the GDP. The Newsweek article actually makes the case for the inevitability, and the fiscal wisdom of, “killing Granny.”8,9

So, we have only two pragmatic alternative systems:

1) Stop treating a large fraction of the population for chronic or costly illnesses and focus all our resources on diseases which can be definitively and cost-effectively managed. This sounds good, but leaves us forever trapped in a cruel world of stunted, or absent medical progress, and beset with a population suffering and dying, without hope.

Figure 9: Some examples of definitive, curative, high technology medicine. Stem and gene cell therapy are now in the early stages of being developed, and will constitute the first wave of ‘regenerative medicine.’ If the current rate of technological progress is sustained, it seems reasonable to presume that the first autonomous cell repair technologies will begin to see laboratory application by the closing decades of this century with mature applications coming sometime in the opening decades of the 22nd century.10

2) Change how we spend our money, and focus on developing definitive medicine. Definitive medicine means controlling aging and addressing and treating the cause of disease at the molecular level, where it originates.

Until we have definitive medicine (which will happen incrementally, not suddenly) we  need a cost effective way to manage patients with maladies that can only be halfway treated, or not treated at all. That means we need to develop truly reversible solid state suspended animation (SA). Within the past few years, a technology has been developed that allows for deep subzero cooling of organs and tissues without any ice formation occurring. This is possible because high concentrations of cryoprotective agents – antifreeze compounds exactly like the ethylene glycol and propylene glycol used in automotive radiator antifreeze – reduce the probability of ice formation and propagation, and at high enough concentrations, these compounds can prevent ice formation completely, even at the slow cooling and warming rates that are necessary to transfer heat out of and back into and large masses of tissue, such as human organs, or human beings.11-14

Because ice formation is inhibited, further cooling of the system results in increasing viscosity until, finally, the solution becomes so viscous that it has solidified. The point at which the system makes the transition from an ultra-viscous liquid, to a molecularly arrested glass (the glass transition point, Tg), is the point at which essentially all chemical and biological activity is halted. This arrest of chemistry occurs independent of the temperature, and is a consequence of the immobilization of the chemical reactants in the glassy substrate of the cryoprotectant-water mixture. The conversion of an aqueous solution into a glass is know  as vitrification, from the Latin word vitrum, which means glass.

As a result of recent advances in vitrification technology, it is now possible to vitrify entire organs.15,16 However, a significant remaining problem is to inhibit ice growth during re-warming in some tissues that do not equilibrate well with the cryoprotectant chemicals. This ice formation occurs as a result of the generation of ultramicroscopic ice nuclei during cooling, which cannot grow or propagate, because there is too little energy in the system, and too little time for ice to grow as a result of steady and continued cooling to Tg.17 While this is a significant hurdle to be overcome, it is a technological, rather than a theoretical one. Additionally, virtually all research on reversible vitrification of organs has been conducted on the kidney, and this presents a unique challenge, because the interior of the organ, the renal medulla, is very poorly circulated. It is thus difficult to load a sufficient concentration of cryoprotectants into this poorly vascularized tissue to completely avoid ice formation.

Figure: 10: Visual appearance of ice in a rabbit kidney that was cross-sectioned during rewarming. The kidney was perfused with a cryoprotective mixture called M22 at -22°C, cut in half, immersed in M22, vitrified at -135°C, and eventually re-warmed at ~1°C/min while being periodically photographed. Times (1:30 and 1:40) represent times in hours and minutes fom the start of slow warming. The temperatures refer to ambient atmospheric temperatures near the kidney but not within the kidney itself. The upper panel shows the kidney at the point of maximum ice cross-sectional area, and the lower panel shows the kidney after complete ice melting. Both panels show the site of an inner medullary biopsy taken for differential scanning calorimetery in order to determine the actual concentration of cryoprotectants in the tissue with high precision. [http://cryoeuro.eu:8080/download/attachments/425990/FahyPhysicBiolAspectsRenalVitri2010.pdf?version=1&modificationDate=1285892563927]

A fair summary of the current technological state of the art is that it is likely now possible to place complex mammalian organs, such as the rabbit kidney, into indefinitely long suspended animation, with little or no loss of viability, and no damage as a consequence of structural disruption due to ice formation. The use of radio frequency, or microwave illumination to speed rewarming, the use of warm gas (such as helium) to perfuse the organ’s circulation, or a combination of both, may offer a workable solution to the problem of ice formation during rewarming. The point is, we are now palpably close to a fully reversible technology for inducing suspended animation in complex living systems. Perhaps most impressively, one mammalian kidney has survived vitrification and rewarming sufficiently intact to permit immediate support of the rabbit from which it was removed (as the sole kidney), until the animal was sacrificed for evaluation 29 days after the organ was re-implanted.

SA brings the cost of caring for any patient down to ~$1K dollars per year, and accomplishes something that most people find very satisfying in life; namely giving their intractable problems to someone else to solve. Since we are already sending our bills for our health care to the future, it only seems reasonable that we should send ourselves along, too.Figure11: The first kidney to survive vitrification shortly before it was removed from the animal for evaluation after supporting its life as the sole kidney for 29 days.

The problem of aging will be a difficult one to solve, and answers will come in iterations that unfold over the remaining decades of this century (providing we make this problem a priority – or survive as a technological civilization). While no well informed scientist would argue that controlling (and even reversing) senescence is impossible, or even unlikely before the turn of the century, no responsible scientist would argue that we understand aging in the way the Wright Brothers did flight at the dawn of the last century. There is a huge difference between a technological problem, and a theoretical problem. Flight in 1907 was a technological problem, as was interplanetary rocketry in 1937: the theory was there, but the technology wasn’t.

Figure 12: The first sustained heavier-than-air human flight, on 17 December, 1903.

Today, with respect to suspended animation, we are more or less exactly where Orville and Wilbur Wright found themselves after they first achieved sustained heavier-than-air human flight, on 17 December, 1903, and where Goddard and Von Braun were in 1937 in terms of achieving space travel. We now have a full understanding of the theoretical requirements for suspended animation, we have a solid proof of principle (mammalian organs have recently been reversibly cryopreserved), and what remains to be done is to develop and expand the technology. Once medicine has SA, it has a cost effective means to offer the promise of definitive therapy to almost every dying patient, at a fraction of the cost currently expended to deliver futile, halfway, or custodial care.

Figure 13: A rough estimate of the cost for induction of suspended animation in humans, followed by indefinite maintenance at ~135oC until such time as definitive medical treatment, including mature regenerative medicine to treat aging, becomes possible. (Estimate prepared by the author using current costs of cryonic cryopreservation at the Alcor Life Extension Foundation in Phoenix, AZ; with assumed reduction in costs as a result of economies of scale in long-term cryogenic care).

Physicians, politicians, bioethicists – they are all confronted with a looming practical and moral catastrophe, and a difficult choice to make. It would appear that the reasonable and humane choice is to fund and perfect the only research that offers the prospect of indefinitely stabilizing care to virtually all dying patients: reversible human suspended animation. That is the most pragmatic, humane and cost effective solution to the inadequacy of, and the problem of, universal health care. Quality, satisfying, universal health care coverage is eminently affordable, indeed it is a trivial societal expense the instant halfway, futile, end of life, and custodial care are subtracted from the package. We can do that humanely with SA, or inhumanely with restrictions on care. There really isn’t any middle ground.


1)      Gupta, S. Cheating Death. Grand Central Publishing 2009. ISBN: 044650887X

2)      Thomas L. The technology of medicine. In: The Lives of a Cell. New York, NY: Viking Press; 1974:31–36.

3)      Silver, JK, Wilson, DJ. Polio Voices. Santa Barbara: Praeger Publishers. 2007 p. 141.

4)     Wilson DJ. And they shall walk: ideal versus reality in polio rehabilitation in the United States. Asclepio. 2009;61(1):175-92.)

5)     Smith, JS. Patenting the Sun: Polio  and the Salk Vaccine. William Morrow & Co; 1st edition. 1990. ISBN-10: 0688094945.

6)    Juskewitch JE, Tapia CJ, Windebank AJ. Lessons from the Salk polio vaccine: methods for and risks of rapid translation. Clin Transl Sci. 2010;3(4):182-5.

7)    Bookchin,  D, Schumacher,  J. The Virus and the Vaccine, Macmillan, 2004. ISBN 0312342721.

8)    Office of the Actuary in the Centers for Medicare & Medicaid Services annually produces projections of health care spending for categories within the National Health Expenditure Accounts, National Health Expenditure Projections 2009-2019: http://www.cms.gov/NationalHealthExpendData/downloads/NHEProjections2009to2019.pdf.

9)    Chernew, ME, Baicker, K, Hsu, J.The Specter of Financial Armageddon — Health Care and Federal Debt in the United States. NEJM (10.1056/NEJMp1002873) was published on March 17, 2010, at NEJM.org. http://healthpolicyandreform.nejm.org/?p=3170. Retrieved December 23, 2010.)

10)   Freitas, R. Nanomedicine. 1999: http://www.nanomedicine.com/NMI.htm.

11)   Fahy, GM, Wowk, B, Wu J. Cryopreservation of complex systems: the missing link in the regenerative medicinesupply chain. Rejuvenation Res. 2006; 9:279-91.

12)   Wowk, B, Fahy GM. Toward large organ vitrification: extremely low critical cooling and warming rates of M22 vitrification solution. Cryobiology. 2005; 51:362.

13)   Wowk B, Fahy GM. Ice nucleation and growth in concentrated vitrification solutions. Cryobiology. 2007; 330.

13)  Wowk, B, Thermodynamic aspects of vitrification. Cryobiology 2010; 60(1):11-22.

14)   Fahy GM. Vitrification: An overview. In: Liebermann J, Tucker MJ, eds. Vitrification in Assisted Reproduction: A User’s Manual and Troubleshooting Guide. London: Informa Healthcare 2007; (in press).

15)   Fahy GM, Wowk B, Wu J, Paynter S. Improved vitrification solutions based on predictability of vitrification solution toxicity. Cryobiology 2004; 48:22-35: http://cryoeuro.eu:8080/download/attachments/425990/FahyImprovedVitriSolns2004.pdf?version=1&modificationDate=1285892436630

16)   Fahy, GM, Wowk, B, Pagotan, R, et al. Physical and biological aspects of renal vitrification. Organogenesis 2009; 5:3, 167-175: http://cryoeuro.eu:8080/download/attachments/425990/FahyPhysicBiolAspectsRenalVitri2010.pdf?version=1&modificationDate=1285892563927

17)   Fahy GM. The role of nucleation in cryopreservation. In: Lee REJ, Warren GJ, Gusta LV, eds. Biological ice nucleation and its applications. St. Paul: APS Press 1995; 315-36.

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