Steven B. Harris, M.D.

In September of 1988, Steve Harris, M.D., published an essay entitled The Day the Earth Stood Still: Cryonics and the Resurrection of the Mythic Hero. It was one of his best in a formidable roster of insightful articles that he wrote dealing with the likely cultural requirements and cognitive limitations that inform humanity’s acceptance, or lack thereof, of cryonics.  I strongly recommend cryonicists read it. Steve’s articles had a great deal of influence on my thinking,  and both Steve and I were, in turn,  influenced by  the philosopher-mythologist-historian Joseph Campbell. I don’t know how Steve was introduced to him, but I first heard of Campbell as a result of the PBS series THE POWER OF MYTH WILL BILL MOYERS, (downloadable here)  which aired in the late 1980s.

I remember breaking out in goose bumps (I have them now) many times during Campbell’s program and, subsequently, when reading his books. His book of the same title as the series is an excellent introduction to his work. I had the same reaction when reading  Steve Harris’ brilliantly insightful articles dealing with issues critical to human perception of, and reaction to cryonics when I read them for the first time in manuscript form, before they were published in Cryonics And I had it again when I read them in “in print” as the final, published product. These works bear reading and rereading and reading again.

The Dead Ant Heap & Our Mechanical Society: http://www.alcor.org/Library/html/DeadAntHeap.html

The Return of the Krell Machine: http://www.grg.org/charter/Krell2.htm

Will Cryonics Work?: http://www.alcor.org/Library/html/probability.html

The Society for the Recovery of Persons Apparently Dead: http://www.alcor.org/Library/html/PersonsApparentlyDead.htm

Many are Cold But Few Are Frozen: http://www.cryocare.org/index.cgi?subdir=&url=humanist.html

Frankenstein and the Fear of Science (Lecture), VHS tape: http://www.worldcat.org/title/frankenstein-and-the-fear-of-science/oclc/043933281

There are very powerful ideas and insights in these essays which should be a source of influence and inspiration to many more cryonicists, than to those relatively few who have read them, to date.

One of my central points about the reason for the continued “failure” of cryonics, and for its very slow growth, both absolutely and relatively,  is the near total lack of any kind of memory of what has gone before, let alone a sorting out of what part of that history is vitally important to be remembered. It’s as if most cryonicists live only in the present, looking forward to a future exclusively of their own imagining, with just a dim halo of memory extending, perhaps 5 years back, at most.

A few days ago, I had my nth practical example of that. I was contacted by some people interested in establishing cryonics Elsewhere. One of the interesting (and depressing) things they had been told by “cryonics people in the US,” was that it was a “good idea to establish companion for profit and non-profit organizations” to carry out the various functions of the cryonics undertaking with minimal liability.

Really?

Maybe that is the best system, but if it is, there is no evidence I know of to support it, and substantial empirical evidence to refute it.

This is an edited version of my response t0 that recommendation:

“I can only tell you what I have observed here over and over again. Maybe you can figure a way around it, or maybe you won’t have the same problems in the first place, owing to cultural differences. I just don’t know.

You will notice that all of the cryonics organizations in the US consist of fully integrated providers. Suspended Animation is the (recent) exception. What’s remarkable about this situation is that it is the polar opposite of what all of us intended when we started cryonics operations here (myself included). There were always paired for profit and not for profit companies, and for just the reasons you’ve stated. CSNY & Cryo-Span, CSC & Cryonic Interment, BACS & Trans Time, IABS & Soma, Cryovita, Manrise & Alcor… And yet there are only single entities around today. Why?

I do not know about your local law, but in the US, it is forbidden for non-profit organizations (NPOs) and for-profit corporations (FPCs) to have interlocking directorates. In fact, it is generally prohibited for corporations related to, or doing business with each other to have interlocking directorates, unless one is mostly or wholly owned by the other, regardless of their status as FPCs, or NPOs. The reasons for this are many and are deeply rooted in corporate law, but mostly can they be reduced to “conflict of interest” issues. In the early days of cryonics, this ban on interlocking directorates was flagrantly disregarded. The inevitable result was that the FPCs completely dominated the NPOs. In fact, FPCs used the NPOs as a convenient shill for doing all the things that were unprofitable, risky, or otherwise not desirable, such as being stuck with the open-ended custody of the patient!

While the initial reason for this was the use of the Uniform Anatomical Gift Act (UAGA) to accept the patients, the eventual reason for it became (obviously), proprietary interest. People in the FPCs got paid for their work (usually in shares in the FPC) and people in the NPO didn’t – couldn’t, in fact. Valuable work, work that would earn shares, got done by the FPCs, and everything else got shuffled off onto the NPOs. You can actually  see this happening at the time, if you take a look at the issues of “Life Extension”/”Long Life Magazine” on the CryoEuro Wiki, because people didn’t talk about BACS, they talked about Trans Time… And where the reward, or the potential for reward exists is also typically where all the time, attention and money will flow.

Eventually, as visibility increased, the state began to menace, and the directorates were fully separated. That’s when all hell broke loose! The people running the NPOs had to be disinterested directors, and they did not stand to make money (or shares), or gain in any way from giving advantage to the FPCs. Contracts, fee increases, and all the other “taken for granteds” between the FPCs and NPOs were now up for debate and consideration. And since they were now two truly separate organizations, jealousy, resentment, and plain old proprietary interest and territoriality took over.

I pretty much thought the FPCs would win, primarily because they did have that huge advantage of proprietary interest on their side. But what I hadn’t figured on was the patients! The NPOs had control of the patients; and it was with the patients that the real loyalties ultimately rested. TT and BACS pretty much destroyed each other. In the case of Alcor, Alcor prevailed, and in the case of CI, well, there was never an issue in the first place, since CI was always an integrated operation. And yet, why this happened remains a mystery to many, even to those who have put some effort into finding out what happened.

In a large, diverse and robust marketplace, commercial service providers servicing NPOs could possibly work. SA may be the first of these, but only time will tell.

However, while cryonics is small and not subject to normal market forces, the two organizations model has not been proven workable. It becomes particularly vicious when there is only one service provider and one NPO, but totally different directors (as the law here requires), because then it becomes like a long-married couple who hate each other, but because of children, fiances and other reasons, cannot divorce. Far from creating the checks and balances it was anticipated to, this set-up created a state of gridlock and animosity. Ultimately, it degenerated to people on both sides screaming that the other was trying to screw them. And since they couldn’t stop dealing with each other and go to the “competition,” it just ground on until there was little or nothing left. That is, in fact, in significant measure, how Alcor was reborn.

Finally, you will encounter this problem: the FPC will be absolutely essential to the NPO, because the FPC will hold all the assets for delivering the up-front (immediately legally riskiest) part of cryopreservation (CP). They will own the equipment, employ the people, own the vehicles…. So the NPO eventually finds itself not just held hostage to FPC , but at risk if the FPC screws up.

I’ll give you a highly personal example. I was a major shareholder in Cryovita, the service provider to Alcor, but Jerry Leaf held most of the shares. Alcor relied on Cryovita completely for rescue and perfusion and there were no alternative service providers available – none. Alcor didn’t own so much as a cannula, or a set of scrub clothes. Cryovita was a shares corporation and the shares were distributed in a complex and potentially problematic way. It seemed possible that if Jerry were to suddenly experience medico-legal death, that the continued smooth functioning of Cryovita could be at risk of being disrupted. That became one of several causes of a major split between Jerry and I, because I realized, as President of Alcor (which I was, at that time), that if Jerry dropped “dead,” Alcor’s ability to deliver CP could be at risk of disruption. Alcor didn’t have cash lying around to go buy all the required equipment in a hurry! It had taken Jerry and me many years to patiently accumulate it, and to do so at well below market rates.

But it was worse than that, because over the years, Cryovita had generated patents, made exclusive agreements, and otherwise done all kinds of normal business things that corporations do. The problem was, all that “stuff” was also needed and used by Alcor! So, I began acquiring those same capabilities for Alcor, which was, of course, a costly duplication of capital equipment and it caused a feeling of resentment in Jerry/Cryovita.

So, what actually happened when Jerry did have a heart attack and was CPed? Well, exactly what I thought might happen, but in a way I never could have imagined. Cryovita did split from Alcor (kindly selling Alcor some of the most critical assets Alcor needed to stay in business), but the people who took Cryovita away were Kathy Leaf (Jerry’s widow), Saul Kent, Paul Wakfer, Brenda Peters and myself – the very people who had been the most ardent advocates of Alcor for so hard and long.

What happened to Cryovita? Well, it morphed in various ways, but today it is known as 21st Century Medicine!

Naturally, this version of events will be strongly biased by my point of view, so I would suggest you ask others and check it out for yourself. Look at the back issues of “Life Extension” and “Long Life” magazine on the CryoEuro Wiki to get a feel for the “Trans Times” of the 1970s and ’80s. Jim Yount, John Day and especially Frank Rothacker of ACS, may also be able to provide you with valuable perspective.”

My guess is that almost all of the newcomers to cryonics over the past decade, or so, have not read any of Steve Harris’ essays. And they clearly know little of the actual history of cryonics, let alone have any distillation (regardless of the direction of its bias) of what is important in that history to remember and act upon.

If you Google “history of cryonics” this what comes up on the first page (and subsequent pages offer no greater resources). Ben Best’s article is actually the most popular (longitudinally). It’s a fine, bare-bones factual narrative. But it is bloodless and lesson-less; it provides no instruction for others striving to create cryonics without recreating our errors. [I want to be very clear here that this is not a criticism of Ben's article: it was not written to be a tutorial on the lessons to be learned from the history of cryonics.]

What makes history both “teachable” and “leanable” is the humanity of it. We are, as Campbell so eloquently said, “story creatures”; we learn through guided narrative informed by the power of the mythic. BACS, TT, CSNY, Cryo-Span, Alcor, Manrise, CI, these entities were created by individual people for very personal reasons, as well as for the visible and easily understood public ones. Most contemporary cryonicists seem to recoil from any consideration of the “messy” and “untidy” aspects of the personal motivations and dynamics that drove (and drive) organizations, in and out of cryonics. And yet, that’s where a lot of the most important reasons and answers are to be found that will lead on to successes, or doom us to repeated failures.

Screening for the Risk of Deanimation

The term “screening” is used in medicine to describe routine examinations or diagnostic procedures of a defined group of individuals to identify diseases or risk factors for same at an early stage. Screening is usually categorized as a  “preventive medical examination” or a  “checkup,” and its aim is to increase the life expectancy of those examined  by reducing the incidence or severity of life threatening disease and enhancing the quality of life. The most accurate examination methods possible should be used to identify as many diseases as possible still in their non-symptomatic phase, so that early treatment or change in life style can be initiated.

It is critically important to understand that the purpose of a “deanimation screening scan” (DSS) is not primarily to interfere with the course of disease or to extend the duration of life during this life cycle. Rather, it is to predict or to warn of impending  deanimation with increased accuracy and precision. Any contemporary medical or health benefits are thus incidental. Indeed, it is precisely when DSSing is used to determine or influence current medical interventions that it becomes dangerous. Knowing when you are likely to deanimate with greater precision, for sole purpose of improving your cryopreservation, carries little if any risk of iatrogenesis beyond that which would be present if you found out you were dying at a later time, or didn’t find out and suddenly collapsed in cardiac arrest from a heart attack, or suffered a massive stroke. It is only when the course of treatment is altered by obtaining the data, or looking at it (see “The Black Box of the Baseline,” below) that DSSing becomes either a practical or an ethical conundrum.

The first problem we confront in a screening test for deanimation risk is that we are moving in completely uncharted waters. We have no benchmarks or baselines on which to structure our screening program, save for a modest number of pilot programs that have been undertaken to evaluate full body scanning as a primary tool for the detection of cancer and atherosclerosis in the general population, or in selected subpopulations. For now, these will have to serve as the basis for our protocols, as well as the important cautionary lessons learned from other screening programs.

For reasons of safety, (see Radiation & Risk, below) Magnetic Resonance Imaging (MRI) is preferred over Computerized Tomography (CT), because no ionizing radiation is employed in making the image. MRI has some important limitations at this time, most notably only a few centers have devices that image the coronary vessels with sufficient precision  to allow risk  assessment for coronary artery disease (CAD).  Similarly, screening for Alzheimer’s Disease (AD),(beta amyloid deposits) also requires CT-PET scanning and the associated exposure to ionizing radiation.  So, for the present, CT is the only way to screen for CAD and AD. For this reason, and for those who for economic reasons may need to use CT imaging, it is worthwhile to briefly discuss the much hyped “risks” of radiation from whole body CT scans and this is done in some detail below.

Figure 25: Typical finding in an elderly woman who under prophylactic full body MRI scanning during a clinical trial in Germany to determine if full body scanning would reduce morbidity and mortality from cardiovascular disease and cancer. (Gohde, et al.)

A specimen imaging protocol is presented as Appendix 1 and is taken from the study by Gohde, et al., “Prevention without radiation – a strategy for comprehensive early detection using magnetic resonance imaging,” which was itself a pilot study in the use of MRI as a screening tool for cancer and cardiovascular disease.

The Mechanics

Currently, there is only one way to get a  DSS and that is to do it yourself.  There are several reasons, which will be discussed directly, why that is not a good idea, or certainly not the ideal way  to pursue DSSing. There are a number of reasons for this, starting with the potential for harm. Primum non nocere is the first dictum in medicine: first do no harm. Information is the most powerful force in the universe and information concerning you own health and welfare is especially important. It is also information that you cannot be objective about. It just isn’t possible. It is for this reason that no good physician treats himself or his immediate family in life or death matters as the sole or usually even the primary caregiver. In fact, speaking from experience as a person knowledgeable in medicine, I have found that wise counsel and advice I can (and do) easily give to others  is strangely absent from my own ears when I am the patient.

This lack of objectivity is more than a nuisance, it can be truly dangerous; and here I will have recourse to an actual example. The first four people to undergo DSSing have done so over the past 11 months. These were all individuals who were over 60 and who had not had consistent (or recent) “physicals.” All were counseled about the dangers of VOMIT and about the negative psychological impact of potentially finding out “something was wrong.” All four individuals had significant anomalies on their scans – two of which were life threatening and these were (or are) being medically managed.

In the other two cases, the scans revealed anomalies that might merit further medical evaluation in testing, and in both cases, the decision was wisely made not to pursue those tests. Why? That’s a complicated question, and I’ll answer it by explaining the circumstances of one of these people:

Mr. Ling is an 82 year old man who is in excellent health. He is physically active, mentally sharp and still working part time in his profession of many years.  He underwent a DSS five months ago. The findings were, overall, very good. His coronary calcium score was roughly a third lower than expected for his age, he had no signs of neoplasms, or of peripheral or central atherosclerosis, and the only abnormal cardiovascular finding was evidence of mitral valve regurgitation, which was deemed not serious and not likely to progress rapidly. However, a number of nodules were found in his right lung, along with some enlarged lymph nodes. The radiologist who reviewed the scan suggested a possible biopsy, with or without “bronchoalveolar lavage” (BAL).

While Mr. Ling is in good health, he is an 82 year old man and BAL requires sedation with propofol or a similar drug, and carries with it the risk of significant complications.  As to a CT-guided needle biopsy of the lung masses or the lymph nodes, this is this discussion that took place between Mr. Ling and the radiologist who interpreted his scan: “OK, let’s consider what this could be? I’m not sick – never felt better, so it’s not TB or something infectious? And if it’s cancer, well, what kind of treatment options would I have at my age for lung cancer with lymph node involvement?”

Those were great questions, and as it turned out, the radiologist was only playing it safe – he doesn’t want to get sued if Mr. Ling finds out he has cancer and a lawyer says to  a jury, “The doctor who imaged him said, ‘You’re in you 80s, I see this kind of thing all the time. Don’t worry about it.”  The radiologist ended by noting, “Since you are planning on following up in a year with another scan, we’ll see if anything has changed then.” And Mr. Ling is fortunate to have sufficient financial means that if he wants to pop in for a scan two months later, he can do that, too.

The problem is, most people aren’t in Mr. Ling’s position, and many will be unable to reason their way past the information that they have “masses” or “lumps” in their lungs and “enlarged lymph nodes in their chests!” That kind of worry cannot only be expensive, it can be damaging to one’s health, and corrosive to one’s quality of life. The information from DSSing should be given in the proper context, in the proper way, by the proper people, with the proper knowledge.  Absent that, it can do real harm. And if the scan does reveal a grave or untreatable medical condition, then there is all the more reason for the person to have the necessary resources at hand to help him cope and plan.

Ideally, this program would be part of a comprehensive Member Survival Program (MSP) administered by the cryonics organization (CO) and there would be a staff person whose job it would be to maintain communications with members, encourage compliance with MSP protocols (including the preferred imaging protocol) and collect and manage the resulting data stream.

Under such a scheme, upon intake (approval of cryopreservation arrangements) all members would have (at their option) completed a comprehensive health history and demographic information questionnaire, most of which would be completed as part of their membership application. The data from this questionnaire, as well as any electronic medical records the member may choose to provide, would be entered into the CO’s comprehensive member data base. The availability of this data would then allow for downstream refinement of the “one size fits all” scan protocol being proposed here, by allowing for individual risk assessment for CVD and cancer. This would flag members at elevated risk of early onset of these diseases to consider commencing scanning surveillance at an earlier age.

The Schrödinger Scan: the Black Box of The Baseline

Unless otherwise indicated, the first (baseline) scan would be done at age 45 for men and age 50 for women. In order to completely avoid any deleterious negative psychological effects, as well any potentially harmful effects from VOMIT (as discussed above), the baseline scan remains blinded and unexamined for 1 year after it is made. This done by providing written instructions to the radiologist reviewing the scan to seal the report unless there are unequivocal findings of life threatening pathology.

At the end of the year long blind period, the scan is examined and any anomalies noted. If the member chooses, a repeat scan can be done to resolve any questions or concerns raised by the baseline imaging. For example, if what appears to be a suspicious mass or nodule was found, a rescan a year later will very likely disclose if it is a neoplasm e.g., it will have grown or spread). It may seem counter intuitive to not look at data which you have paid for, experienced inconvenience to get, and which “might” save your life, but that is the necessary price that must be paid for this intervention to be used safely.

The baseline scan must be regarded as the first part of something that will not “happen,” or be completed for another year – like a bulb that has been planted to bloom in the spring, or a bond that will not mature for another 12  months. The scan itself is only a part of the process: the necessary information to safely interpret it does not appear until the required interval of time has elapsed. After all, before this protocol was proposed, no one ever got scanned and they felt just fine about it (until they dropped over in cardiac arrest).  For those of a quantum bent, consider it an extended version of Schrödinger’s famous experiment, except instead of the cat in the box, it’s a CAT scan in the box.

Scan Intervals & Exceptions

If the baseline is “negative,” showing no evidence of evolving pathological processes that merit intervention or further monitoring, then it is being proposed that the next scan take place 5 years later. Similarly, with each subsequent negative “healthy” scan, the next scan would be 5 years hence until age 81, at which point scans would be done every 2 years until cryopreservation ensues.

Figure 26: Proposed algorithm for Deanimation Screening Scan intervals and actions.

These scan intervals are arbitrary and will no doubt need to be refined over time as experience is gained. Intuitively, it seems that there should be a relationship between scan intervals and increasing age, and it is possible to configure scan intervals based on things like increasing risk of SCA or terminal illness with age. However, until some real world experience is gained, a conservative approach which minimizes costs and maximizes the opportunity for benefit, seems best. There are lots of programmers, mathematicians and similarly qualified people in cryonics and if any are interested in working with me, I am interested in generating scan interval algorithms based on the rising risk of disease and death with age (if you are interested, contact me at m2darwin@aol.com)

Going it Alone?

If a decision is made to proceed with DSSing on an individual basis, there are a number of important things to keep in mind and to do:

* Do consider carefully the possible impact this decision will have on you and on your family. In fact, give some thought to discussing this with your spouse or significant other before moving ahead.

* Do select a good imaging center with competent and caring staff who can give you good counsel about the procedure and the results. Imaging centers that offer full body scans are often used to counseling patients: make sure the one you select is a good one. Talk with the staff about your concerns before you commit to being imaged.

* Do explain to the radiologist who will interpret your images that you are having a baseline scan done and you only want to know if there is unequivocal pathology present that requires immediate or urgent medical intervention. If you can’t get that assurance from him, ask for your results only in writing on the same disk on which your scan is written.

* Don’t look at your scan or the written report that accompanies it. If you have a reliable and willing CO, send a copy to them and ask them to send you the results a year from when they receive the media with the images and the report on it. Duplicate CDs are typically made and given upon request at no charge, or for a small fee at the time you are imaged, or when you come for your results. Bring your own media to save money!

* Do provide a copy of the disk with the scan on it to your medical surrogate and to anyone who is on you ICE (in case of emergency) contact list on your mobile phone. The reason for doing so is that, should you experience SCA during the blinded waiting period, the scan may still save you from autopsy if it documents the presence of CAD, or some other pathology that could have caused your sudden and unexpected deanimation.

* Don’t  rely on the DSS to keep you out of trouble, or to reassure that everything is OK, should you develop serious health concerns. Just because a scan shows no indication of pathology does not necessarily mean that there is none. If you have signs or symptoms that would have prompted medical attention absent scanning, act on them in the same way after scanning. Let your physician decide if the scan is significant in the context of any illness or concerns.

* Don’t forget that the scan intervals are 5 years and that is more than enough time for serious disease to develop. Indeed, the 5 year window is a long one, especially where cancer is concerned. A DSS is not a health promotion or a disease prevention program. It’s primary purpose is to let you know you are terminally ill, not to assist you in avoiding that eventuality.

* Do know that if you have atherosclerosis, “vasculopathy” and you want to monitor progression of the disease, your scan intervals will have to be much shorter than 5 years – probably 6 months to 1 year, depending upon the severity, your response to medical intervention, and so on.

Economies of Scale?

Medical imaging is a highly competitive, non-monolithic industry consisting of many operators, large and small, both independent and institutionally affiliated. Such market environments inevitably encourage the drive to survive, and thus typically offer the discriminating consumer the opportunity for real bargains. I made a number of calls to imaging centers around the US and discussed the possibility of group discounts and “scan plans” wherein members of an organization or group, even just a group of like minded individuals, could get deep discounts on scans. The majority of centers I spoke with were receptive to this idea, and several discussed specific numbers which were anywhere from 20% to 60% lower than their standard walk-in fee.

Thus, it should be possible for groups of cryonicists in a given geographical area to make arrangements with a local imaging center for scans. The same was also true when I inquired about group or institutional discounts for carotid and abdominal ultrasound screenings, with the difference being that in some cases, prices went from ~ $350 per screen to ~ $60 per screen, providing the group could be scheduled for the same time and place.

The Pre-Cryopreservation Baseline CT Scan

Figure 27: A hypothetical pre- and post-cryopreservation  CT cerebral angiogram. The post-perfusion image would be obtained by administering radiocontrast agent(s) into the perfusate immediately, or shortly before discontinuing cryoprotective perfusion, prior to deep cooling to storage temperature.

If it is at all possible, a final vital CT scan of the head (at least) should be done as close to the time of cryopreservation as possible. This scan should be done with contrast and with no concerns about clinical radiation dose limitations, since the member will be terminal. The objective of this scan is to document, in as much detail (highest resolution) possible, the morphology of the brain and its vasculature. The imaging technique used should be one that optimizes resolution of the cerebral angiogram. The reason for making these images is that they should allow for many important determinations about the quality of initial stabilization and cryoprotective perfusion and cryoprotectant distribution in the brain to be made, at leisure, during the period the patient is in storage.

If contrast agent(s) is injected into the perfusion circuit shortly, or immediately prior to the discontinuation of perfusion, it should be possible to obtain a post-vitrification angiogram, which in turn should allow for evaluation of cerebrovascular patency, as well as assist in determining the anatomical landmarks within the cryopreserved tissue. It should also be possible to add other kinds of tracers to the perfusate, which might allow for quantification of regional distribution of cryoprotectants, or of other molecular species of interest not only within the brain vasculature, but within the brain parenchyma, as well. Again, the presence of a baseline pre-cryopreservation scan will likely be of great importance in allowing accurate interpretation of post-cryopreservation images.

This scan must be a CT, as opposed to an MRI, since MRI scans are unobtainable in deep hypothermia, or in the solid state.

Radiation & Risk

When the mass media talk about the “risks” from radiation associated with CT scanning, the first question that should spring to mind is, “Risks to who?” Sensitivity to ionizing radiation varies based on the cell age and mitotic cycle, and what this means in practical terms is that the younger you are, the greater the risk radiation presents to you.  Children thus have a much higher relative risk when compared to adults due to their rapid cell division and cell differentiation rate.

Figure 28: The risk of developing cancer as a result of radiation exposure is strongly age dependent and decays dramatically as people age. By the time an individual is in his 60s, 70s or 80s, the risk of neoplastic disease from medical imaging becomes negligible. Adapted from ICRP Publication 60 (1990).
 

These data also demonstrate that you cannot simply use the average relative risk shown in Table 1 to estimate the increased incidence of cancer due to radiation exposure. In order to do this analysis correctly, you need take into consideration the age of all individuals in the irradiated group. For instance, a man of 80 has a life expectancy of about 8 years, versus 33 years for a man of 45. Thus the risk to individuals over the age of 70 is, for all practical purposes, essentially nil. Table 2 illustrates what the  American College of Radiology considers minimal to high radiation doses in “absolute” terms.

This is why there is an increase in the relative risk values for the “entire population”  if children are included in that evaluation. However, even a quick glance at Figure 28 (above), where the estimated lifetime risk that radiation will result in cancer (carcinogenesis) is presented relative to the person’s age, shows that children have a 10% – 15% lifetime risk from radiation exposure, while individuals over the age of 60 have minimal to no risk (due to the latency period for cancer and the person’s life expectancy).  The accepted latency period is, by the way ~ 10 years.

Table 1 shows the relative risk of developing cancer per sievert (Sv) unit of radiation exposure. Tables 3 and 4 provide some comparison benchmarks of radiation exposure both in relative terms (low, medium, high) and in terms of common, specific medical imaging procedures used in regional CT.

So, let’s put this information in the context of a cryonicist wishing to reduce his risk of unexpected deanimation. The protocol being proposed here assumes a baseline scan at age 45 for males (50 for females) which, if free of any indication of ongoing morbid processes, is to  be repeated in 5 years, at age 51. If than scan is negative, subsequent scans would be performed at intervals of 5 years (if negative) until age 81, at which time the scan interval would decrease to 2 years. If we assume a lifetime cancer risk of approximately 1 in 1000 and a total of 7 scans  until age 81, at which point any further risk from radiation exposure becomes irrelevant, we might expect to see an increase in the lifetime risk of cancer from approximate 33% to 34%.  Even if the number of scans were more than doubled to 20; one per two years during the interval between age 50 and age 80, the lifetime risk of cancer would increase at most to ~ 35%.[1] This of course, assumes that all DSSs are CT, as opposed to MRI.

These risk calculations are based on the linear no-threshold (LNT) model of radiation risk.  This model assumes that the carcinogenicity of radiation is proportional to dose, even down to the lowest levels.  No one really knows how carcinogenic low-dose radiation is, because the carcinogenicity of low doses is so small that it’s practically impossible to measure. The official position of the Health Physics Society is that quantitative estimates of risk for doses below 50 mSv per year (100 mSv lifetime) cannot be made.[2]

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As useful aside, if you are interested in the progress being made in medical imaging, I would highly recommend the blog Magnetic Resonance Imaging: To See and Be Amazed: http://limpeter-mriblog.blogspot.com/ The site contains many beautiful images and is a treasure trove of information on both the mainstream progress, and the esoterica of MRI

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End of Part 4

(ischemia) ~85% of the time!

By Mike Darwin

Removing a Central Objection to Cryonics

In case you missed it, what I just said in that slim paragraph at the end of the preceding part of this article has profound implication because it has the potential to remove what is unarguably one of  the largest and the most rational objections that there are to cryonics. That objection is that roughly two-thirds of those who have made cryonics arrangements will not be cryopreserved under good conditions, and that half of all those signed up will be cryopreserved under very adverse conditions, such as autopsy or long (greater than 12 hours) post cardiac arrest delay. The recent advances in non-invasive medical imaging I’m about to discuss here offer the opportunity to we cryonicists to make many, if not most such losses all but unnecessary.

Figure 17: False color CT 3-D reconstruction of a patient’s intracranial arterial vascular tree. The orange-red, cheery shaped anomaly behind the right eye is a large aneurysm. The brain and other intracranial soft tissues have been digitally subtracted to facilitate a complete and unobstructed view of the patient’s arterial vasculature.

The image that you see in Figure 17 is now a perfectly pedestrian medical image that can be obtained from a garden variety CT scanner available at most diagnostic imaging centers in mid-sized cities anywhere in the world. This particular image has the brain, the soft tissue and everything digitally subtracted from it but the patient’s arterial tree and skull. The cherry shaped protrusion on the right is an aneurysm which, if were to rupture, could cost the patient his life or leave him profoundly disabled.

Figure 18: Many brain aneurysms can be treated non-surgically by passing a very thin platinum wire within the aneurysm where the wire coils up to form a yarn-like ball inside the weakened, ballooned-out area of the vessel wall. A clot subsequently forms around the coil and the vessel eventually closes off the opening to what was once the aneurysm.

Fortunately, there is a procedure  called “coiling” (Figure 18) which allows most such aneurysms to be successfully treated. Sadly, very people with brain aneurysms know that they have one until it ruptures – by which time it is almost always too late treat it effectively.

Scan Your Troubles Away?

The question logically arises, “Why not look inside everyone’s head if we have the technology to do so? Wouldn’t that allow us to identify not only the people who have aneurysms they don’t know about, but also everyone who has a tumor, or a narrowed coronary or carotid artery, or a gallstone, or anything else wrong with them that they don’t know about? In fact, why not scan their whole bodies and see if anything is amiss? Wouldn’t that allow us to nip most slowly progressing degenerative diseases in the bud?”

The answer to that question is a qualified “Yes and no.” The first and most important qualification to consider is the very substantial difference between them and us. They are going to die and, hopefully, we are not. Once you are content to die, it doesn’t really make a great difference exactly how it happens and it certainly doesn’t make any difference what happens to you afterwards. They will pay exactly nothing to avoid laying around dead for x-hours, or to avoid being autopsied. We, on the other hand, will pay something. That is a huge divide, because, as it turns out, the first and greatest barrier to such universal screening using CT and/or MRI is its adverse cost to benefit ratio.

Figure 19:  The rapid advance of computing and the high demand for ever more sophisticated medical images has driven the cost of 3-D CT and MRI scanning down to ~ $200 for a head scan $800 for a whole body scan.  http://www.superiorbodyscan.com/?gclid=CP_d5Neyiq8CFWwGRQodsHQX-w

While there are many CT and MRI machines, they are kept adequately busy, or perhaps just a little less busy than some of their owners would like, imaging sick and the worried well or hypochondriacal people. If the entire population, or even some modest fraction of it were to suddenly present for imaging, the system would crash. CT and MRI machines are very expensive and while the cost of scans has dropped dramatically, they are still not free. On the macro-level, governments, insurance companies and economists are constantly struggling to determine which therapeutic and diagnostic interventions offer the best return for the money invested in them.

The Problems of Bite Back and VOMIT

Surprisingly, information obtained from diagnostic tests can sometimes not only fail to yield any benefit, in which the case the money spent on the test is wasted, they can also cause harm. A recent example of this, much in the news, is the Prostate Specific Antigen (PSA) test used as a screening tool for prostate cancer (Figure 20). (http://www.pbs.org/newshour/rundown/2011/10/psa-testing-controversy-reignites-over-screening-debate.html) The problem with the PSA test as a screening tool is that to be effective in that capacity it requires a fairly long baseline, a good deal of contextual information (the patient’s race, family history, medications, and so on) and it requires good clinical judgment as well as a ‘patient’ patient.

Figure 20: It was anticipated that the PSA test, used as a screening tool for prostate cancer, would significantly reduce both the morbidity and mortality from the disease. It has so far failed to do so.

A single high PSA reading, or even several, may mean nothing. Most often it is the trend, rather than the absolute number; this is particularly true for black men.  In short, it’s a test that takes a lot of time and thought to interpret and use well and as such is probably not well suited to mass screening where a “yes” or “no” answer is sought before proceeding to costly, invasive and possibly injurious further evaluation.  Yet another problem is that even when prostate cancer is found and treated, it turns out that very few lives are saved because most of those cancers are slow growing and in men who will die of something else before the cancer kills them. Thus, the cost to benefit ratio of the PSA is being questioned, not the least of which because it causes many men to suffer and even die from treatments from which they did not benefit!

This is very much where medicine is today with respect to the “medical imaging singularity.” While it is possible to “look inside” just about everybody, the cost to benefit ratio for the health care system and for the “man on the street” would not justify it. In fact, it would be a medical catastrophe.

To understand why this is so it is necessary to understand three things. The first and most important of these is something called VOMIT, which is a very serious form of bite back associated with our new found ability to see inside patients with increasing exactitude. VOMIT stands for Victim of Medical Imaging Technology and refers to patients who suffer unnecessary interventions for abnormalities observed by imaging or other investigational technology, but which were not found during surgery or subsequent invasive diagnostic interventions. (Hayward, 2003) Here, I will go further and extend the definition of VOMIT to include any diagnostic finding which result in a diagnostic or therapeutic intervention which is not cost effective or causes harm to the patient. That is a very important caveat and tall order to fill, as we shall soon see.

The second is the relatively straightforward one of the ratio of the dollar benefit of resources expended to dollar benefit returned in years of productive life saved as a result of the intervention. Even in cases where early diagnosis saves lives, such as in breast cancer screening, the economic returns are equivocal. It is also often the case that “early” diagnosis with existing imaging technology is still not early enough to cure the disease. As a result, the patient suffers a longer, more miserable course of treatment and the healthcare system is subjected to greater expense with no return.

The third is the problem of information overload and it is somewhat related to VOMIT. The truism that a picture is worth a thousand words is probably a vast understatement. A single 3-D medical image contains a vast wealth of information – information which has heretofore been unavailable to both the clinician and his patient.  This might seem like a good thing, and in the long run it will be, but for now, and for a long while to come the details of the landscapes being revealed will, to a great extent, be terra incognito.

The Danger of TMI

When advances in microelectronics allowed for 24-hour ECG monitoring in the 1970s,  it became possible for clinicians for the first time to see the beat by beat electrical activity of their patients’ hearts for up to a day at a time, or longer. Prior to that, they were limited by the enormous quantities of paper tracings that would be required and the need to confine the patient to the clinic or laboratory. Now, with the advent of the compact and mobile “Holter monitor,” it was possible to capture the patient’s ECG data continuously under ambulatory, real-world conditions (Figure 21). Physicians were awash in a veritable sea-tide of data!

Figure 21: The Model 445 Mini-Holter Recorder which was released in 1976 allowed clinicians for the first time to “see” their patients’ ECGs under real-world conditions and for prolonged periods of time.

The problem was , they assumed, quite understandably, that they knew what it all meant. After all, doctors had been looking at patients’ ECGs for decades in their offices, in hospitals, at bedsides in homes and in physiology laboratories. They knew how to read  an ECG! So, when they discovered that some of their patients had periodic bouts or “runs” of very worrisome arrhythmias, they did the prudent and rational thing – they treated them for these arrhythmias with medications. Unfortunately, the result was the opposite of that expected; a significant increase in morbidity and mortality in these patients, because it turns out that in a subpopulation of healthy people, those arrhythmias were benign and not indicative of any health problem.  Thus, misinterpretation of the “same” information they were confident in dealing with in small chunks, presented in bulk and in a different context, was one of the unforeseen and arguably unforeseeable bite back consequences of Holter monitoring technology. (Harrison, 1978)

The Last Heart Attack?

If you assemble and then read over the Alcor case summaries of the last 40 years it is impossible not to be shocked by the seemingly high incidence of sudden and unexpected cardiac arrests. Because my data set is incomplete for Alcor, I can’t be definitive, but the number seems to be somewhat higher than for the same subpopulation of people from the general population (white, middle class, etc). Until, that is, you consider that most cryonicists are male. So, as you read accounts of cryonicists in their 40s and 50s arresting while scuba diving, while taking a nap or watching television, in part what you are seeing is selection bias at work. The point is, no one ever died of “sudden heart disease” a “sudden aneurysm” or, for that matter “a sudden cancer.” These are degenerative disease that takes years to decades to develop. While still difficult to detect in their nascent stages, their terminal lesions are usually very visible many months and sometimes for even for many years before they end lives.

Figure 22: Coronary artery calcium scoring using computed tomography and carotid intima media thickness and plaque using B-mode ultrasonography offer the prospect of detecting almost all coronary artery disease before it reaches the stage where it can cause a heart attack or sudden cardiac arrest.

There has been a great deal of media attention lately to an initiative called SHAPE; The Society for Heart Attack Prevention and Eradication,  which aims to all but eliminate heart attacks by combining CT of the heart to obtain a “myocardial calcium score” (a powerful risk predictor of heart attack)(Figure 22) and carotid intima media thickness and plaque using B-mode ultrasonography as part of a three step program to eliminate heart disease. The next two steps in SHAPE’s plan are a “polypill” combination of blood pressure and anti-atherosclerosis drugs and finally, perhaps, a vaccine. A similar “Last Heart Attack in America” initiative focused on coronary scanning along with dietary interventions to reverse atherosclerosis has been the focus of a feature length documentary on CNN in which former US President Bill Clinton is prominently  featured as a spokesman and advocate. The common ground of these two initiatives is that almost no one dies of a heart attack without there being  glaring evidence present in their hearts years before the infarct occurs. It is only necessary to look for it!

There can be no question that as imaging technology evolves, and as medical acumen catches up with what is available, that such imaging will become a routine part of any checkup  for patients whose age and risk profile merit it (and eventually, if they live long enough, that means most patients). As it stands right now, if you are a middle aged man or woman with a significant risk profile for heart disease, and you have a heart attack, it’s my personal opinion you have ample grounds to sue your physician for negligence.  Right now, that’s just my opinion, so it doesn’t count for anything, but the point is that sooner or later this, or a better coronary imaging modality is going to become the standard of care and heart attacks will become a rare event – a thing of the past – a relic from a time when doctors couldn’t see inside of you.

Ultrasound Investigations

There are cheaper, simpler and completely risk free ways (in terms of radiation) to  find out whether you have atherosclerosis or not.  The most predictive of these for money is the carotid ultrasound (CUS) test.

Figure 23: The carotid ultrasound scan is  a simple, non-invasive diagnostic investigation that employs sound waves to create an image of the two large blood vessels in the neck that supply most of the blood to the brain. If there is a buildup of plaque or a thickening of the limning of these two arteries the person is at increased risk of stroke and there is a high probability that there is also systemic atherosclerosis present. If there is evidence of severe narrowing of one or both of the vessels, then it becomes urgent that medication and possibly surgery be used to correct the condition in order to avoid the likelihood of a crippling or lethal stroke.

This simple, non-invasive test takes just a few minutes and uses ultrasound waves to image the carotid arteries and the blood flowing through them (Figure 23). If there is thickening of the arterial wall, or plaque present, then it is a virtual certainty that the person has systemic atherosclerosis and warrants a more extensive workup. This test is often also “packaged”  with a quick “look-see” at the abdominal aorta also using ultrasound, to rule out the possibility of an abdominal aortic aneurysm – something that is more common in smokers once they reach middle age, and beyond.

If you shop around diligently, the cost a CUS can be as little as your transportation costs to the health fare or community center where it is being offered, often as a “loss leader” by health care providers or medical imaging companies seeking more remunerative business opportunities (if they find something amiss during the CUS).  The cost of such an evaluation can range from as little as $60, to as much as $380.

A CUS is ideal for people on a budget and for those under age 45 with no history of heart disease, cancer or other pathology or risk factors that might put them at increased risk of sudden cardiac arrest.

Why Full Body Scans?

Figure 24: The full body CT or MRI scan is often offered as “add-on” to the complete or the “executive’s” physical. Many imaging centers offer these scans without the need of the patient’s person physician prescribing the scan using their in-house radiologists to write the order for the test. http://www.prevenium.com/contact.asp

 Put simply, there is no substitute for seeing, or to put a new twist on an old adage: a picture is worth a thousand medical tests. While the origins of all of the degenerative diseases that kill us are at the molecular level, mostly we die as a consequence of the macro-level changes they inflict on our bodies, even if the coup de gras is rooted in the action of things like adhesion molecules and inflammatory pathways; as is the case with most heart attacks. It is the large, easily “seen” bulges of aneurysms, masses of plaque or tumor that kill, and these almost always take years to develop. What this means practically is that, with a few exceptions, aside from suicide, homicide and accident, virtually no one has to die – or to deanimate without plenty of advance warming. The implications for cryonics are as obvious as they are profound.

End of Part 3

(ischemia) better than ~85% of the time!

By Mike Darwin

Ischemia: The Problem of “Long Down Time”

 Almost every cryonicist I’ve ever spoken with envisions his cryopreservation will occur under ideal circumstances. He will be diagnosed with  some vague and ill defined terminal illness, bravely decide to end futile treatment and then enter hospice with a team of skilled and caring cryonics personnel at his bedside. He will nap, read, watch TV, and then, near the end, nod off surrounded by loved ones as the cryonics personnel hover nearby. This may not be the most attractive picture in any absolute sense, but it is certainly as reassuring a one as it is possible to find in contemporary cryonics. And while many, or even most cryonicists may find this scenario credible, much of the rest world doesn’t.

 Figure 10:  Approximate U.S. distribution of predictable deaths by cause based on 2004 data. Note that ~57% of all deaths occur sufficiently suddenly, or under circumstances such as accidents, which preclude standby or other cryonics stabilization measures. Chart derived from data: [National Vital Statistics Report, Volume 53, Number 5 (October 2004)]. This data may be compared to the data in Figure 10 to see how closely the US national incidence of sudden and unpredictable death map that of Alcor’s experience (Figure 11).

One likely reason for the scarcity of biomedical people involved in cryonics is that their actual, day-to-day experience is at sharp odds with the scenario I’ve just laid out above.  In countless hours of both focused and casual conversations with such individuals, what emerges is a sense of incredulity about the reversibility of the damage these professional and technical people witness as a part of their duties caring for the very old, and the critically ill dying; not to mention that large fraction of people who die suddenly and without warning, end up as DOAs in the emergency department or coroner’s cases. Regardless of whether their opinions prove the valid ones, we are clearly failing to communicate to them and to the community at large, an experience of cryonics which is not so biomedically adverse.

To do that, it is first necessary to move beyond  anyone’s scenarios or suppositions and evaluate the reality of what is actually happening to the patients we cryopreserve. That turns out to be a hard thing to determine with any degree of precision, because none of the cryonics organizations maintain any kind of statistical database on their members’ cryopreservations. How many cryopatients have dementia? How many were autopsied? What is the mean ischemic time from cardiac arrest to the start of cardiopulmonary support (CPS)? How many patients have ischemic times of 2-5 minutes, 5-10 minutes, 15-30 minutes, 12 hours, 14 hours, 5 days? What is the mean age at cryopreservation? [Absence of data on this last question I find particularly amusing in a group of people supposedly preoccupied with longevity and "life extension": how long are they living, on average?]  There is currently no way to tell.

There is not even any way to determine the age, gender, or any of dozens of other potentially critically important demographic details that are, or could be vital in assuring quality cryopreservations, reducing ischemic times, or reducing known iatrogenenic events. A concern of mine for onto three decades now is that we have no way to spot adverse epidemiological events that might be associated with our unique dietary supplement or other lifestyle practices. Perhaps most incredibly, there are no written criteria, however arbitrary, to assign any degree of quality, or lack thereof, to the cryopreservation a given patient has received (let alone that a given Cryonics Organization (CO) provides, on average). This had lead to what has become known as “the last one is always the best one” to date rating system, wherein each case that is not either an existential or an iatrogenic disaster, is pronounced by the staff who carried it out as, “the best case we’ve done so far!”

We cryonicists may be in some kind of willful, data free fog about what our situation is, however, it’s a safe bet to assume that most of the rest of the world, based on their own professional and personal experiences, are not so ignorant. The first step towards a solution is to understand the scope and severity of the problem by getting reliable numbers. While that is not easy to do, the Alcor Life Extension Foundation does maintain a crude, if incomplete accounting of all the patients they have placed into cryopreservation: http://www.alcor.org/cases.html. A cursory analysis of this yields the following breakdown. Even basic data such as cause and mode of death are missing from ~20 of the cases listed there – these have necessarily been excluded from the analysis below.

Figure 11: A major hurdle to evaluating quality in cryonics operations is the lack of any outcomes (e.g., reanimation followed by evaluation) or of any surrogate markers or scoring systems to serve as evaluation tools to determine not only the quality of cryopreservation care being given, but also the objective neurocognitive status of the patients when they enter cryopreservation. For the purposes of this analysis very crude criteria were used to assess the quality of the patient as a finished product at the end of cryopreservation. These were normothermic ischemic time between cardiac arrest and the start of CPS, catastrophic peri-arrest brain injury such as an intracranial bleed followed by prolonged cerebral no-flow before pronouncement of medico-legal death, very long warm ischemic times (> or = to 12 hours) and autopsy.

Using the criterion of “minimal ischemia” (≤15 minutes)[1], 48% of Alcor’s patients are cryopreserved under these conditions (Figure 10).  Thirty-nine percent of their patients suffer long ischemic periods of 6-12 hours or more (mostly as a result of SCA and UDA); and 13% suffer very long periods of ischemia (> or = to 24 hours) which are not currently preventable, or which conclude in autopsy prior to cryopreservation.  Put more cogently, you have less than a 50% chance of being cryopreserved (with Alcor) under conditions of minimal ischemia. While this number is discouraging, it is spectacular when compared to the Cryonics Institute, where it is somewhere in the low single digits.

Figure 12: The graph above is the same as in Figure 11, with the difference being that the losses have been expanded to include those that would be expected if the population wide incidence of end-stage, GDS-7 dementias were imposed on all the groups. The result is that percentage of patients who might reasonably be expected to have both minimal ischemia and no pre-cryopreservation GDS-7 dementias drops to just 26%.

But once again, these numbers are misleading if the criterion is cryopreservation under minimal ischemia conditions, because they do not take into account the number of patients who enter cryopreservation with dementia, or severe brain injury due to stroke, other neurovascular disease, or massive head trauma. If only dementia, at the current incidence for the general population is factored into the analysis, then the picture becomes considerably more bleak, as can be seen in Figure 10, with only 26% of  Alcor cryonics patients being preserved with relatively intact brains under reasonably good conditions.[2]

Impact of the BDDs on the Likely Survival of Personhood

Figure 13: The effect of advanced Alzheimer’s Disease on the macroscopic appearance of the brain is evident when coronally sectioned brains from an AD (R) patient and a healthy person in their mid-20s (L) are compared side by side.

Deaths from AD are typically deaths from end-stage AD, which usually implies severe global destruction of both cerebral hemispheres (Figures 13 & 14) on both a macro and microscopic level. Death due to AD is a prolonged process (~8 years from diagnosis to death), and the neurological deterioration that occurs as the disease progresses is often scored using the global deterioration scale (GDS) of primary degenerative dementias, which ranges from 1 (least) to 7 (worst) in severity. GDS scores in excess of 5 are associated with major loss of macro- and micro-scale brain structure and will be assumed here to represent serious compromises to, or the destruction of personhood.

Figure 14: The histological appearance of the brain in AD is shown in panels b and c above. In many areas of the brain there is virtually complete loss of the neuropil; the synaptic weave that interconnects neurons which can be seen in its normal state in c, the panel at the far left. The majority of the neurons and many of their supporting glial cells have died and been scavenged by macrophages and histiocyytes.  There are abundant deposits of proteinaceous plaque containing the  neurotoxin protein beta amyloid neurofibrillary tangles which are the remnants of neuronal long processes such as axons and dendrites. The extent and uniformity of the changes seen above varies from patient to patient during the course of the disease, but becomes increasingly uniform throughout both hemispheres of the cortex the longer the patient survives with a GDS score of 7 (end stage dementia).

A Deanimation Warning Device?

Figure 15: The medical imager as a deanimation prediction device?

 In his 1939 science fiction story Life-Line,” Robert Heinlein envisions a device that can predict, with considerable precision, when a person is going to die. While none of us cryonicists wants to die, most of us could certainly profit from knowing when we are going to deanimate. Better still would be also finding out how to postpone our cold dip in liquid nitrogen for a while, if it was possible to do so.

Many cryonicists will be familiar with this graph of Ray Kurzweil’s showing the impending arrival of the singularity (Figure 16).

Figure 16: Ray Kurzweil’s graph showing the exponential increase in neuro-image reconstruction which has occurred largely as a function of the exponential growth in computing capacity since 1970.

Well, if you are a cryonicist, I’m here to tell you that insofar as non/minimally-invasive medical imaging is concerned, the singularity is here.

From the earliest days of medicine physicians have desired one thing almost above all others and that is to possess the power to peer into their patients bodies and observe the goings on there. Since the discovery of x-rays by Wilhelm Conrad Röntgen in 1895 (Crane, 1964) there has been steady progress towards the satisfaction of that desire. The development of contrast media, endoscopy, computerized axial tomography (CAT or CT) scanning and magnetic resonance imaging (MRI) scanning have allowed increasingly exact and impressive images of the interior of the living body to be made.

However, a number of serious limitations have, and to a great extent still do prevent the full realization of the physician’s idealized desire to see inside his patients at will. Those barriers are field, dimensionality and point of view, as well as resolution, color, contrast and the dollar cost of the imaging.

In the case of CT and MRI those barriers have been breached to such a degree that it is now possible for cryonicists to be able to determine with a very high degree of accuracy and precision both of what and when they are going to experience medico-legal death. A corollary of this is that in many cases it will be possible for them to avoid what would have otherwise been an unavoidable very long period of ischemia and quite likely a medico-legal autopsy  as well.

End of Part 2

How to avoid autopsy and long ‘down-time’

(ischemia) better than ~85% of the time!

By Mike Darwin

It’s easy to concentrate on the biggest and most obvious reason that cryonics hasn’t attracted wider acceptance, principally the fact that it doesn’t work “yet” and it will be a long time before we know if does. But there’s a clue to another capital reason for its slow adoption which is to be found in the failure of cryonics to attract much enthusiasm or activism within its own ranks. Why is this?

I believe a central reason for this failure is that cryonics, even as it is currently configured and accepted by those who embrace it, performs dismally. Everyone seriously involved with cryonics is painfully aware, either consciously or subconsciously, that cryonics is at least a two tier lottery. Sure, everyone knows that we’re taking a “chance” on being recovered in the future by being cryopreserved in the first place. But to even get to that round of the lottery, you have to get cryopreserved, and it would seem material whether or not you are cryopreserved well.

For some, perhaps cryonics is a ritual exercise. As long as there are remains, a freezer, someone to take the money and hang picture on the wall, then you have a chance; and all chances are created equal. Their position seems to be same as that of the millions of lottery ticket holders before the winning number is announced: we all have the same chance at the prize. If that’s your attitude, you can stop reading this right now, there’s nothing more here to interest you – not even in terms of idle entertainment value, because this discussion, from here on out is deadly serious, and brass tacks practical.

 Figure 1: The autopsy rate has declined by half in the United State between 1972 and 2007, although it has shown a slight increase since these data were collected. Source: http://www.cdc.gov/nchs/data/databriefs/db67.pdf

As Figure 1 shows, the autopsy rate, which can serve as the ultimate, population wide indicator of a very bad cryopreservation,  constituted 8.5% of all deaths in 2007. That percentage has risen slightly since then and is now at ~ 9%. The situation isn’t quite as grim as it might first appear if you break down the reasons for autopsy and note that 55.4% of autopsies were conducted as a result of deaths due to “external causes,” which means suicide, accident or homicide. If you think you are in a “lower risk” category for these, you may  be right, in which your case your risk may be fractionally smaller. And of course, not all of these autopsies were state mandated: some were requested by the next of kin, or even the decedents themselves. Still, 9% seems a reasonable, overall unavoidable loss number currently confronting cryonicists given the culture we inhabit.

Figure 2: Since the first man was cryopreserved in 1967, the demographics of autopsy have shifted increasingly from the aged to those in younger population cohorts. Source: http://www.cdc.gov/nchs/data/databriefs/db67.pdf

If the age distribution of autopsies in the US is examined, the picture gets even more uplifting if you are, or you expect to live in into old age (which is, incidentally, medically defined as 65 years of age, or older). In this age group, the incidence of autopsy has declined dramatically from 37% of all postmortems since 1972,  near the time cryonics began, to only 17% as of 2007.

However autopsy is only one of a number of factors that can and do interfere with  cryonicists achieving “good,” or even “acceptable,”  (forget  ideal), cryopreservations. The other three factors which loom large are sudden cardiac arrest (SCA), unexpected death (UD, which is different than SCA) and brain destroying diseases ( BDDs, or dementias). While Alzheimer’s Disease is the most common of the BDDs, there are others such as Pick’s, Lewy Body, Parkinson’s and the vascular dementias, which together account for 20-30% of all age-associated BDDs.

Brain Destroying Diseases (Dementias)

Autopsy is only one of a number of factors that can and do interfere with  cryonicists achieving “good,” or even “acceptable,”  (forget  ideal), cryopreservations. The other three factors which loom large are sudden cardiac arrest (SCA), unexpected death (UD, which is different than SCA) and brain destroying diseases (BDDs).

 Figure 3: Incidence of dementias as a percentage of all cause mortality in males, females and the United States population as a whole. Prepared from data in the National Vital Statistics Report Volume 59, Number 10 December 7, 2011Deaths: Final Data for 2008: 2008http://www.cdc.gov/nchs/data/nvsr/nvsr59/nvsr59_10.pdf

 Currently, the BDDs in aggregate (including catastrophic stroke) account for ~3.2% of all deaths in the US (Figure 3). However, insofar as cryonicists are concerned, this number is likely to be misleadingly low, because most cryonicists enter cryopreservation at or after age 65, the point at which the incidence of BDDs begin to climb exponentially. (Evans DA, 1990) This number is expected to, and in fact is exploding as a consequence of both the demographic shift due to an aging population in the West and increasingly longer life spans (Figure 4).

 Figure 4: The large increase in Alzheimer’s Disease as a cause of death in the United States is largely a function of the increasing average age of the population and the survival of many additional individuals into advanced old age. Source: http://www.alz.org/downloads/Facts_Figures_2012.pdf

 Figure 5: A breakdown of dementias by type shows that Alzheimer’s Disease accounts for 47% of the total as the sole cause of the dementia and is a major contributing factor in another 28% making it by far the most common pathological mechanism in play as the cause of dementia in the elderly.  [S. Seshadri, S, Wolf, PA, Beiser, A,  Au, RU, McNulty, K, White,R, et al. Lifetime risk of dementia and Alzheimer's disease: The impact of mortality on risk estimates in the Framingham Study. Neurology, 49:1498-1504,1997.]

 Figure 6: Incidence of Alzheimer’s Disease by age cohort in the US population as of 1988.[ Evans D, et. al. Prevalence of Alzheimer' s Disease in a community population of older persons. JAMA, 262:18;2551-6, 1989.]

In the 74-84 age cohort, 19% of that population has AD (exclusive of other dementias) and in those individuals over the age of 85, the diagnosed incidence is 47%. These numbers are almost certainly low, because many of the elderly are who are institutionalized for falls, or other issues not ostensibly related to primary brain disease, go on to develop brain disease in an institutional setting and ultimately have listed as their causes of death, pneumonia, urosespsis, sepsis  secondary to decubitus ulcers, or other causes that escape epidemiological surveillance for AD. Currently, AD is responsible for 2.8% of deaths in white males men aged 65  or older and 4.7% of white males who are 85 years of age, or older. These numbers are expected to triple by the year 2050.

 Figure 7: The incidence of Alzheimer’s Disease rises roughly exponentially with age such that over 1,100 people out of 100,000 aged 86 or older have the disease.

When cryonics was launched in the mid-1960s the problem of BDDs as a threat to the workability of cryonics was not even considered.  In 1967, the year the first man was cryopreserved, the average life expectancy in the US was ~70 years and the problem of dementias was a fraction of what it currently is.  Additionally, comparatively little was known about the pathophysiology of the BDDs at that time, and there was little or no awareness within the cryonics community of their potential to degrade or altogether destroy personal identity, perhaps even years in advance of the pronouncement of medico-legal death. The problem of BDDs and of age-associated destruction of the brain is arguably the foremost biomedical obstacle confronting cryonics in the long term, and it is for this reason that I will return to this topic again later in this article in the context of discussing its early detection, with a brief discussion of treatment, and ultimately, definitive interventions to halt and reverse it.

Figure 8: The Siemens Biograph mCT PET is a positron emission tomography/computed tomography (PET•CT) scanner that enables precise measurement of metabolic processes and data quantification, including the assessment of neurological disease and malignant tissues (resolution and molecular characterization of neoplasms as small 3 mm in diameter). The device can provide quantitative measurements of brain beta amyloid protein burden.

For now, I will note that because AD is by far the most common of the BDDs and because it has a unique pathophysiological feature, a remarkable advance in early diagnosis via noninvasive  computerized tomography (CT) and positron emission tomography (PET) imaging has recently become clinical available. Beta amyloid is the protein found in the plaques characteristic of AD, and there has been intensive research over the past decade to identify radiolabeled tracer compounds that will safely cross the blood brain barrier (BBB) and bind to both beta amyloid and tau proteins. (Barrio 2008), (Black, 2004)  In February of this year, the US FDA approved the Siemens Biograph mCT, a positron emission tomography-computed tomography (PET-CT) scanner capable of not only detecting, but of quantifying  amyloid in the brain. The Biograph mCT has been very well received, and within the space of a few months the machines have appeared in most major cities in the US. The Biograph mCT in conjunction with the recently developed FDDNP, (2-(1-6-[(2-[F-18] fluoroethyl)(methyl)amino]-2-naphthylethylidene) malonitrile) tracer allows for calculation of total brain amyloid burden (Wang, 2004) and visualization of discrete amyloid containing lesions as small as ~ 3 mm in diameter (tracers for tau protein, the other primary pathological protein in AD are currently in the pipeline for FDA approval).

 Figure 9: Top: PET scan of beta amyloid deposits in the brain of a patient with early moderate Alzheimer’s disease appear in red in the image above. The beta amyloid deposits are concentrated, as expected, in the frontal and prefrontal cortices as well as in the hippocampus. Bottom: Beta amyloid distribution in the brain of a patient with early moderate AD (L) versus normal control (R). One important consequence of this imaging is the growing realization of the global range of AD’s impact on the brain. As recently as a decade ago it was believed that the destruction of brain tissues was confined largely to the hippocampus and the prefrontal cortex, especially early in the disease. It is now understood that the histological destruction of AD is widespread and that during the end-stage of the disease few if any areas can be expected to be spared.

Very early detection of AD may turn out to be critical to achieving effective treatment, or even slowing progression of the disease, since significant beta amyloid and tau deposition seem to promote ongoing inflammation and interfere with putative therapeutic drugs. A good example of this is the recent fate (Vellas, 2010) of the investigational drug  tarenflurbil ((R)-flurbiprofen ) which inhibits gamma-secretase, the enzyme that produces beta amyloid AB-42, the species of beta-amyloid that forms fibrillary plaques. (Black, 2008) Unfortunately, the drug does nothing to remove existing existing AB42 deposits, which presumably continue to exert their neuron killing and pro-inflammatory actions.

(R)-flurbiprofen is highly effective in animal models of very early AD and the drug showed significant promise in Phase I & II clinical trials. However, development of (R)-flurbiprofen was dropped when it became apparent in Phase III trials that the drug would likely only be effective in a clinical setting if it its administration was begun before clinical signs of AD developed; in other words, when beta amyloid levels were very low and would be detectable only by testing cerebrospinal fluid or, now with sensitive CT molecular imaging techniques involving the screening of subpopulations of healthy individuals at risk.

This kind of effort and application of technology and pharmacotherapy may not profitable for pharmaceutical companies, but that does not mean that it would be be worthwhile for us cryonicists. (R)-flurbiprofen  is a close chemical relative of the OTC NSAID ibuprofen and it is a metabolite of the prescription NSAID flubiprofen.  (R)-flurbiprofen  is an enantiomer of flurbiprofen (~ 5%  of (L) flubiprofen is metabolized into (R) flubiprofen by the liver after ingestion) which is completely inactive as  a COX inhibitor, and is thereby free of the anti-COX side effects associated with NSAIDS.  Despite it’s lack of both COX-I and COX-II activity, the drug does have strong anti-inflammatory activity by acting through inhibition of NF-κB and AP-1 activation pathways, and this may provide added benefit in controlling the inflammatory processes associated with AD. (Tegeder, 2001)  As an interesting aside,  (R)-Flurbiprofen has also been shown to suppress prostate tumor cells by inducing p75NTR protein expression. (Quann, 2007)

(R)-Flurbiprofen is an example of a drug with considerable therapeutic potential that will almost certainly not see clinical application due to the high cost associated with regulatory burden and the logistical hurdle of needing to start therapy years before symptoms of AD manifest themselves. (R)-Flurbiprofen might also conceivably be useful as combination therapy with  the already FDA approved skin cancer drug bexarotene (Targretin), an antineoplastic, which has been shown to reverse beta amyloid deposition in a rodent model of AD as well as to improve cognitive function. Targretin rapidly cleared beta amyloid from the brains of animals in a variety of models of AD (<2 months) and while it is not a cytotoxic chemotherapeutic agent, the drug has sufficient adverse effects that it would be problematic to administer over a period of years or decades. A combination of short term therapy with Targretin to remove beta amyloid, followed by long term administration of (R)-Flurbiprofen is a possible treatment strategy that would seem attractive to explore. The ability to dynamically monitor beta amyloid levels in the brains of patients undergoing such novel therapeutic regimens, especially outside the confines of the medical-industrial establishment, is yet another advantage of this evolving singularity in medical imaging.

End of Part 1

Reception area of the Alcor Life Extension Foundation in Riverside, CA in April of 1987. The photos above the refreshments cart were of some of the patients in Alcor’s care at that time.

Sometimes we get defeated by technology, sometimes by cluelessness and sometimes by a most unexpected intersection of the two.

In 1981 I conceived of the idea of hanging the picture of each patient cryopreserved at Alcor on the wall of the facility. I intended the practice to start, not in the place where it might seem obvious for it to; in the patient care bay (PCB) as a memorialization of the patient for his family and friends, but rather, in the reception area and offices, where the organization’s staff dwelt on a daily basis. It was my intention that as the patients accumulated in the PCB, the photos would begin accumulating in the offices, laboratories, corridors and workspace of the Alcor staff.  The intention was to provide a not so subtle reminder that there were people in those big stainless steel tanks, people who were desperate to get out of there.

Photos of Alcor patients apparently spilling off  (?) the walls in the conference room at the Alcor Foundation’s facility in Scottsdale, AZ in April of 2011. Photo courtesy of Stan Lipin

My intention was that, over time, there would an inverse and very adverse relationship between “success” in terms of patient population growth and “failure” in terms of growth in the number of pictures on the wall. In time, I envisioned (with some glee) the framed photos multiplying like locusts, becoming ever more oppressive and occupying ever more wall space.  I foresaw that they would likely encroach into the PCB. I also thought it likely they would be downsized. But mostly, I hoped they would serve their primary function, which was that each one was to serve as a reminder to those working at Alcor: “Hey, I’m still waiting, get me out of here! I want to get back to living, just like you are, too!”

This was not an idea which I kept secret. It was frequently discussed with other Directors, with staff, even with the officers and directors of other cryonics organizations. In fact, I now believe it is a practice which has become universal at cryonics organizations around the world. Or should I say, had become universal.

Alas, I hadn’t counted on technological advance. Technological advance is almost always a “two sided blade” and is this case, the blade cut in a way I hadn’t at all foreseen. The digital photo frame makes it possible to store essentially an “infinity” of images, and display them all in the physical space occupied by just one, over short sequences of time. In so doing, it removes the clutter, and thus the annoyance of hundreds or even thousands of actual framed, photographic images. One problem solved.

And another created. The purpose of institutions is to attempt to overcome the most damaging consequences of human mortality to civilizations: the destruction of knowledge, wisdom and the values they enable. In short, the loss of memory and accumulated experience that comes with the death of individuals.

Enter the halls of any civilization’s venerable institutions and you will see the images of the individuals they treasure on their walls and of those individuals’ ideas encoded in the books lining their shelves and engraved in the form of quotes and aphorisms on their walls. Stroll their great cities, or the corridors of their museums and you will see statues and likeness of the persons they treasure and admire cast in bronze and carved in stone; all these things are feeble attempts at conserving the ideas and values of the individuals who created the intellectual capital that sustains their civilizations. It is not just that they owe these men personally (they do) it is that these civilizations survive by remembering and living by the ideas that these men created.

Unfortunately, it turns out that ideas, standing alone and absent the context of memory, are weak things. It is one thing to know that fire burns, and another thing altogether to know that fire burns having been burnt by it. It is the power of knowledge in the context of experience that is wisdom, and it is wisdom that is destroyed by death. Knowledge contained in books, or nowadays in digital form, is but a shadow compared to that contained in the mind of a man who knows the real truth of a thing in the context of personal, hard won experience. Feeling, guided by reason over time, is the most powerful tool in the universe; and death is its ultimate enemy.

The human institution (first as oral tradition) followed by the written word, were man’s initial tools against death. Poor instruments that they were, they were used to fight valiantly in an attempt to conserve the memory of what was – a story of people, places and events over time. They were, to a remarkable degree, successful. The Royal Society is almost unbelievable in this regard, with every scrap of correspondence and every minor triumph and squabble being recorded and preserved. So are many neighborhood British garden societies – many going back hundreds of years. This will be true of every successful human institution from enduring religious institutions such as St. Catherine’s monastery in the Sinai, to the fraternal organizations such as the Masons in the US.

Robert Ettinger (left).

With the advent of scientific medicine and Ettinger’s book in 1964, it has become scientifically credible for human beings to reach for personal biological immortality and thus, for the first time, for a credible and a definitive “end to death.” Because what death really is, is the destruction of human knowledge and wisdom, and that is always and necessarily rooted in the destruction of individual humans. Wisdom, in particular, is uniquely a property of individual persons, and so is creativity. Neither of these fantastical properties which create and drive civilization can be distilled into books, carved into stone, or molded into bronze or plastic.

To achieve immortality for individuals it will be necessary to utilize the structure of institutions. It should be abundantly evident that such institutions will necessarily have to be the most stable and durable of those which human beings have so far managed to engineer. As such, they will have to most emulate that property which human institutions were created for in the first place: the conservation of memory of persons, places and events in order to conserve values over time. This why institutions incessantly speak of things like “grand old traditions” and “institutional memory.”  Admittedly, it is a hard thing to do. And it is a perilous thing to do, because it relies upon successful prognostication of the future; that the ideas and values selected for conservation and propagation over the ages are the ones essential for success; and that the ones not essential, do not discredit those that are.

Inherent in cryonics is a terrible arrogance and optimism which attracts a kind of people who seem to possess an inborn contempt for, or incomprehension of the value of the past. This is evident in their own disregard for it. There is a shocking lack of historical conservation at both CI and Alcor. In fact, it is so shocking and all pervasive that I know that my words here will have virtually no impact on almost all who read them, because no one,[1] at either place has any idea of what I’m talking about. It is, literally, the equivalent of talking to people who have never seen books, about how shocking it is that they don’t have libraries.

Organizations that are clueless about their own (recent) historical past should, not surprisingly, also be clueless about the deeper reasons for things like pictures of patients hanging on the walls. A few years ago, I was talking with one of the (many) former Presidents of Alcor who had a question for me about  something in a member’s paperwork. This President wanted to know what “BACS” was? Now, I am old. In fact, I’m a little older than cryonics (by about 9 years). But that still only makes me 56, not 156.  I felt a little like I do when I see anyone in the US being stopped on the street and asked questions like, “Who is the Secretary of State?” or “Who was Abraham Lincoln?” and the response is an utterly clueless answer.

If you’re an average reader here, and you don’t have a clue, that’s OK, because there really is no cryonics community to get acculturated in. The answer is that the Bay Area Cryonics Society (BACS, they changed their named to the American Cryonics Society, ACS, in 1985) was the dominant cryonics organization in the world from ~1974-1984! That’s a third of all of cryonics history and it’s not that long ago.  To not know that and to be running the world’s largest cryonics organization seemed wrong to me. Not because it was wrong per se, but because it was inevitably a marker for what had to be a veritable iceberg of other missing information that was of far greater import. And even that isn’t necessarily a fatal flaw. Realizing a deficiency of knowledge or character or resources, even a spectacular one, and working hard to remedy it is the oldest heroes’ tale in the world.

By Mike Darwin

Me and Mei Lei, settling down after dinner and a peek at the heart of the time machine, which was then kept in a shed in back of the the Chamberlains’ home in La Crescenta, in 1973.

I was an 18 year old kid feeding quarters into a payphone in front of a Piggly Wiggly grocery store at 9 o’clock on a summer night in 1973, in Augusta, Georgia. On the other end of the line was a middle aged aeronautical engineer in La Crescenta, California, not far from the Jet Propulsion Laboratory, feeding me dreams. He wasn’t telling me about the spaceship he was working on to explore the outer planets, instead, we were talking about the time machine he was building to take us to the future. You see, I was helping him with the design – my part was the bubble trap, where pressure and temperature would be measured.

The “front-end” of the “time machine” in 1973, before the bubble trap was designed, fabricated and installed.

The engineer’s name was Fred Chamberlain, and we had met the year before at his home where he, his wife Linda and I had had dinner and had looked over the various parts of the time machine project. It was then that I noticed that the device was missing a critical component – a bubble trap – a device to prevent dangerous air bubbles from entering the circulatory system of the time traveler. Fred immediately saw the importance of the oversight and I set about designing a bubble trap that would fit into the device as he had already configured it.

The glass bubble trap for the “front-end” part of  the “time machine” in use to perfuse Fred’s father in 1976.

We had been in correspondence for several years before we  met. Though I was just a boy, we shared a dream to voyage into space and conquer the stars. To do that, both of us understood we would have to become time travelers, because we were trapped in a time and place that was wholly unsuited to our ambitions and aims. We had been born too soon. We were doomed to grow old and die before our species mastered the technology to venture forth from the world of our birth and set sail into the cosmos. The only way we could see out of this tragedy, Fred, Linda and me, was to become time travelers, in fact to become a very special sort of time traveler – medical time travelers.

Linda Chamberlain in 1974.

What kid, then or now, wouldn’t kill to have a life like that? Isn’t that the stuff that dreams are made of and the juvenile SF novels are plotted around? Nobody has a life like that and everyone knows that a story like that couldn’t possibly be true. Have Spacesuit Will Travel? No doubt. Have time machine? Well, then then you’ll really go places!

The working heart of the time machine!

And yet, every word I’ve written there is true, and I’ve got the pictures to prove it; and you’ve just seen them.

Fred Chamberlain was a NASA-JPL electrical engineer working on the Mariner-Jupiter-Saturn mission in 1973, and we had that conversation and many like it. And we planned the mission Fred began yesterday and many more like it before, and to follow. The time machine we were working on was actually for a “fourth” of us, not mentioned in my story, Fred’s father, Fred, Jr., and it was indeed used to launch him on his journey on 16 July of 1976. And yes, my bubble trap was an integral and a successful component of that mission.

Fred, Jr., and Fred, III, father and son, now time travelers awaiting rescue.

Frederick Rockwell Chamberlain, III was and is of absolutely critical importance to cryonics. While most people with more than a passing acquaintance with cryonics will associate his importance with the founding of Alcor, that is in reality only a surrogate marker for his deeper importance. Fred came on the scene in cryonics in what was unarguably its darkest hour. It had degenerated into little more than a fraudulent cult in California and, everywhere in the US, it had lost all vestiges of technical and scientific rigor.

When Fred discovered this in his role as Vice President of the Cryonics Society of California (CSC) he not only left CSC and founded Alcor, he and Linda Chamberlain established, for the first time anywhere, the practice of scientific, evidence-based cryonics; cryonics based on the scientific method, on documentation of procedures, policies, cryopreservation protocols and rigorous patient case reports. He and Linda mandated not only scientific and technical accountability, but administrative, financial and legal accountability as well.

Standardized procedures, protocols, equipment and meticulous documentation were critical elements Fred and Linda Chamberlain brought to cryonics.

In doing these things, Fred and Linda attracted and mentored others. Fred’s personality and his military background brokered no compromise and his mentoring profoundly shaped me and a few others, molding us into the irascible and generally disagreeable inhuman beings we are today. At one time Fred was responsible for replenishing the tritium supply of all of the hydrogen warheads in the US nuclear arsenal. Men given that responsibility do not suffer fools gladly.

Personally, Fred taught me a great deal about engineering; not about the mathematics of it, but about engineering at the systems level, about how to look at a complex problem and tease it apart without being overwhelmed by it. He had a fantastic ability to see and solve problems at a meta-level, and he was able to communicate that to others.

Fred Chamberlain helped to build three incredible machines all of which had their origin at roughly the same place and at roughly the same time; in the foothills of the Santa Monica mountains near Pasadena, California in the early 1970s. Two of these are the Voyager spacecraft, now on their way to the stars moving  through the heliopause at 16.6 km/s  and 19.4 km/s, even as I write this. The other, the medical time machine begun when I was a boy, even before that pay phone call in Georgia, is, for the moment, located in Scottsdale, Arizona and it is moving relentlessly forward with its precious cargo of time-stopped souls one slow day at a time. Godspeed to all of you!

Fini.

Linda,

 You can believe me when I say that I do have some idea of your loss. Only some, I’m sure. It has been a hell of a last few weeks for me, but nothing to what you’re going through now.

 Man, oh man! I miss him already, and I haven’t laid eyes on him in years.

 I remember all those years ago in La Crescenta, we were so young, and yet we were planning for this very goddamn eventuality. We were actually planning for it, thinking about it, talking about it, working towards it. We knew it would come, and in a weird sort of way, we hoped it would come, because the alternative would be that if it didn’t come for us at all, we would be one of the truly unlucky ones that fell through the cracks, like Marce did. Still, we have his loss to bear for now, and for some unknown seasons of tomorrows yet to come.

Fred (left) cryopreserving his own father, Fred Jr., in 1976.

But remember Linda, it was just yesterday that we planned for this day now so soon arrived – a plan that has been, as we so rightly foresaw, flawlessly executed. Now, let us be patient just a “little” while longer, and work again, just a “little” bit harder, so that we can awaken tomorrow, and find that that other day that we talked about, dreamed about, planned for and worked towards has also arrived, in which we find ourselves together again – not in “paradise,” but in this world, planning for, thinking about, talking about and working towards those other dreams that we had to put on hold, simply in order to survive.

Let us look forward to those goals and dreams and many, many more still undreamt and unimagined, to which we shall again apply ourselves when the tear-blindness of our grief subsides.

 Mike Darwin

Fred Chamberlain III: First Life Cycle: 1935-2012

by Linda Chamberlain

Fred Chamberlain III recently had his brain placed into cryostasis at the Alcor Life Extension Foundation in Scottsdale. His physical presence will be missed by many friends, biological family and chosen family until technology allows a future instantiation to be with us once again.

Among his many talents, Fred wrote inspiring poetry and loved to play the guitar and keyboard. He was one of the most intellectually creative and energetic people I’ve had the privilege to know. He just recently published BioQuagmire, which in my opinion is the best transhuman, life extension novel ever written. Fred (together with me and other authors) published a volume of life extension and transhumanist short stories in the 1980s called Life Quest.

The picture above shows Fred when he was in his twenties working in bomb disposal as a Navy diver. He was interested in ethics and was a strong supporter of Ayn Rand’s ideology. Fred became actively involved in cryonics in 1969 in order to get his father, Fred Chamberlain Jr., suspended (Alcor News, August 1976). Fred and I met and became Forever Buddies in 1970 while working on the committee to organize the second national cryonics conference, held in Los Angeles, CA.

Here we see Fred in his thirties, sitting on the rim of the Grand Canyon. He was an engineer at the Jet Propulsion Laboratory (JPL) in Pasadena, Southern California, where he worked on the Voyager missions to Jupiter and other fascinating projects.

That’s when I first met and fell in love with him. One of our great intellectual and emotional bonds was our interest in technological means of extending life. Fred and I incorporated the Alcor Life Extension Foundation in 1972; the minutes of those early Alcor meetings can be viewed by  those who might be interested. Many details from those early years are available on Wikipedia.

The photo to the right shows Fred in his 60’s when he and I were again active in Alcor between 1997 and 2001.

The picture on the left shows us in 2002 when we renewed our wedding vows on a beach in Cozumel with a traditional Mayan wedding with both of us wearing traditional Mayan wedding dress.

Inspired by the Mindfile tools and programs being developed by Terasem (including but not limited to CyBeRev.org and LifeNaut.com), and seeing Mindfiles as an absolutely essential part of any personal life extension plan, we moved to Melbourne, Florida in 2010 to contribute as much as possible to the Terasem Movement while we remain in biological bodies, and then continue doing so when emulated as cyberbeings. We made a presentation about Cybertwins at Terasem’s 5th Annual Colloquium on the Law of Futuristic Persons in Second Life (on Terasem Island), on December 10th, 2009.

Fred recently had his brain placed into cryostasis at the Alcor Life Extension Foundation in Scottsdale, to preserve his Connectome as additional Mindfile information. Though I will have to carry on alone for both of us for a short while before we see each other in cyberspace, Fred is still part of all of us in the Terasem Collective Consciousness and we will continue to enjoy his warm creativity again soon as well as through his poetry and many writings.

As they say on the Star Pebble, See you in the next cycle.

With all my love,

Linda Chamberlain

To view online with active links: http://www.lifepact.com/OdeToFred.pdf

By Mike Darwin

Left: Science Fiction writer Fred Pohl, with friend.

Predicting the future is a tough business. It is an especially tough business when it is proposed  that the prediction be highly specific and technically accurate. Say, akin to predicting the iPhone with Siri in 1965. It’s often been noted that none of the Golden Age of Science Fiction writers like Heinlein, Clarke, or Asimov predicted the PC, let alone the laptop. And most didn’t have a clue about the emerging developments in biology. So, the odds that one of those esteemed gentlemen would have conjured up a hand-held device that you could ask just about any question to (and get a useful answer), pay your bills through, order your meals with, get directions from, do your banking over, get reminders, entertainment or voice mail from and have a conversation with…well, the odds of that were just about nil. Just about, but not, as it turns out, quite nil.

In his 1965 cryonics novel, The Age Of The Pussyfoot, that Golden Age Science fiction writer, co-contemporary and friend of Bob Ettinger, Fred Pohl posited the existence of a device called the Joymaker, which every civilized person would necessarily have to have. The Joymaker incorporated the following features and uses:

• Access to sophisticated computing for money management, scientific calculations, etc.
• Access to planetary libraries at any time and any place.
• The education of children each of whom have their own Joymakers.
• Health Maintenance: the Joymaker monitors vitals, administers life saving or mood altering medications, summons emergency medical help and summons cryopreservation services in the event of cardiac  arrest.
• The Joymaker offers voice mail which is the core of interpersonal interaction in the novel.
• Orders all food and beverages and arranges payment, both in the home and in public.
• Orders all other goods for delivery and since payment is automatic, the expense of items is not always apparent to the buyers. Thus, the protagonist rapidly depletes his “fortune.”
• Replaces the public address system allowing any group of people to hear a public announcement on their Joymakers thus eliminating the need for loudspeakers in public places or interruption of entertainment programming.
• Locating people. The central computer can track the position of any Joymaker, and by extension, its owner. This information can be made available at the owner’s discretion.
• Jobs not requiring physical presence. One character is a “Reacter,” someone who samples new products and reports her reactions using the Joymaker. The central computer analyzes her reactions in the light of her known psychological makeup and is able to statistically predict how well the product will sell.

Left: Robert C. W. Ettinger, the father of cryonics.

The Age Of The Pussyfoot was set in the year 2527. However, in his Afterword to the novel, Pohl noted that he thought many of the functions of the Joymaker would be realized not in five centuries, but more likely in five decades.  Forty seven years after Pussyfoot, the iPhone with Siri is here, and most of Pohl’s predictions are  indeed a reality.  And, at age 93, Fred Pohl has survived long enough to see his predictions become reality. His friend and fellow science fiction writer Bob Ettinger was cryopreserved late last year and Pohl has been intimately aware of cryonics for ~50 years. He was one of the first people Ettinger contacted about the idea and over the ensuing five decades Ettinger never ceased to nag Pohl to make cryonics arrangements. The two were good friends and stayed in touch in writing – the last letter Ettinger wrote to Pohl shortly before his cryopreservation, admonished him, yet again, to get signed up for cryonics.

I too had tried to persuade Pohl to make cryonics arrangements, even offering him a “free freeze” in 1978. When Ettinger entered cryopreservation on July 23, 2011, Pohl wrote a moving tribute him on his blog “The way of the Future” and this prompted me to take up where Bob necessarily left off in urging Fred to make cryonics arrangements:

Mike Darwin says: Hello, Fred, this is from Mike Darwin, the guy who made you the offer of a “free freeze” after dinner that night in Louisville, KY in our suite in the Galt House hotel. You were the Guest of Honor at the American Science Fiction Convention in 1978, and we took you to dinner and made you an offer that, as it turned out, you easily could refuse! If you want to read an account of that meeting from the perspective of the cryonics people present at that time, it’s up on line, here: http://www.alcor.org/cryonics/cryonics8301.txt and is entitled, “When You Can’t Even Give it Away – Cryonics and Fred Pohl.

When you write about Bob Ettinger, “He wrote me one more letter, good-naturedly urging me to change my mind. That was the end,” I would say in response, “Uh, uh, it is much more likely, on the basis of probability alone, that was the end not for Bob, but for you.

Bob and I talked and corresponded about you a number of times over the years. Unlike you, I was not close to Bob, and we were often at odds. Interestingly, one of the few things that ever resulted in a genuine emotional connection between us was the offer we made to cryopreserve you for free. While he was too reserved and diplomatic to say so, your given reason for turning cryonics down, well, to be frank, I think it pissed him off a little. It was apparent that he genuinely liked and admired you and that, maybe just as importantly, he shared a common past with you. You and he grew up in the Golden Age of Science Fiction and you both shared the common narrative and heritage of what is now being called “The Greatest Generation.” The last time I saw Bob, was over dinner a few years ago in Michigan. He was quite frail, but wickedly lucid. I asked him if you were still compos mente and if he was still in touch with you. He sighed, “Yes,” and a “Yes.” And then he momentarily lost his temper, which is something I almost never saw him do. I don’t remember his exact words, but they were pretty to close to this: “I guess he doesn’t think that much of me or of the rest us, because he’s so worried about being alone and displaced from the people he knows and loves now. Doesn’t he think I’ll be there? Doesn’t he think any of the hundred or so others from our generation will be there? And if he does, and he is so worried about loneliness and social isolation, then dammit why doesn’t he come along to keep us company?”

I thought that was an extraordinarily good question. But logical and emotional arguments aside, it was painfully clear to me that HE WANTED YOU ALONG FOR THE RIDE. I had a hard time holding back the tears, and I had to excuse myself to the men’s room.

When most men die, their probability for any future goes to zero; in effect, their event horizon collapses. That’s about to happen to you (and to me, and to everyone else). Say what you will, Bob Ettinger now confronts two possibilities – oblivion, or one hell of a really interesting future. A future far more fantastic than anything you or he ever dreamed of, or wrote about. If nothing else, just to have come that far and to be in that position, well, it’s a hell of an accomplishment. And I am very grateful to Bob Ettinger for achieving it, because it opens that possibility to me, as well.

So, Fred, here’s the deal. Your friend is waiting for you: he damn sure wanted you to embark on the adventure (good or bad) that he has now begun. In fact, he kept at you to go until, literally, almost his last breath for this life cycle. He can’t do it anymore, so I guess it is my turn, once again, to ask you to reconsider and to join your friend and colleague on his journey into the land you both dreamed of when you were young, and in your salad days. Please, reconsider your arguments. It is now for sure you won’t be without a friend and cohort, and I can pretty much guarantee you that your revival won’t take place unless you have a use.
Finally, I can tell you for a fact that the best use you have is continue living and growing and telling stories. At our core, we humans are ‘store creatures,’ and we will remain so as long we *are* human. It goes without saying that story creatures need storytellers; your job is thus secure.

August 2, 2011, 11:47 pm

To which Fred replied:

Declining Immortality Twice

Mike Darwin’s response to my piece on the loss of that very good man, Bob Ettinger, caught me completely unaware. I am grateful to you for repeating the offer of a free freeze, Mike, just as I am grateful to the people who sometimes tell me that they’re going to pray for me. Even though I can’t accept your offer, it’s a kind thought.

Let me quote from a poem that was written long ago by John Dryden, in an attempt to sum up the teachings on this subject of the even longer ago Roman philosopher Lucretius. The last six lines say it all, but I’ll give you the whole thing. It goes like this:

So, when our mortal forms shall be disjoin’d.
The lifeless lump uncoupled from the mind,
From sense of grief and pain we shall be free,
We shall not feel, because we shall not be.

Though earth in seas, and seas in heaven were lost
We should not move, we should only be toss’d.
Nay, e’en suppose when we have suffer’d fate
The soul should feel in her divided state,
What’s that to us? For we are only we
While souls and bodies in one frame agree.

Nay, though our atoms should revolve by chance,
And matter leap into the former dance,
Though time our life and motion should restore.
And make our bodies what they were before,
What gain to us would all this bustle bring?
The new-made man would be another thing.

But I do appreciate the offer.

This entry was posted on September 9, 2011 at 12:30 am at http://www.thewaythefutureblogs.com/2011/09/declining-immortality-twice/

Fred Pohl may be the first man in the history of the world to have declined a shot at immortality not once, but twice! I would argue that the really amazing thing about Pussyfoot is not just that Pohl got the technology of the Joymaker right, but that he also got the biotechnology of the future more or less right – granted in no small measure due to that “good man” and good friend of his, Bob Ettinger.  Fred Pohl knew a sound and reasonable idea when he saw one , biological or otherwise,  and 50 years later cryonics has endured and the biological basis for it has grown steadily better. Lucky patients cryopreserved with little or no ischemia, using the best available vitrification techniques today, will have intact connectomes and minimal neuronal molecular damage. Such fortunate patients will suffer virtually no freezing damage.

Above: The Connectome.

 Any yet, Pohl is having none of it.

Right: Viktor Frankel.

I used to find this a mystery. To be surprised by it. To marvel at it. However, that time has long past. The first insight that offered a partial answer to that mystery came from Viktor Frankel’s book, Man’s Search for Meaning.  Frankel noted that there were two basic types of people in the concentration camps – those who drew their sense of identity and purpose from their social/societal position; husband, father, lawyer, doctor, mother, grandmother… and those who drew it from some other source, independent of their social context, or how they were labeled. For some, the origin of that sense of identity was religious, for others, it existed independent of any institutional or religious thoughts or beliefs. Those few people saw themselves as unique and worthwhile individuals deserving of and entitled to life and survival at all costs, independent of any external factors or forces.

Much later I realized that another component in the will to survive that is often material in making the choice for cryonics is the yearning to be transcendent. It is not enough to be able to see the future with accuracy and precision, it is necessary to yearn to be it. To quote Nietzsche:

 ”I teach you the overman. Man is something that shall be overcome. What have you done to overcome him? … All beings so far have created something beyond themselves; and do you want to be the ebb of this great flood, and even go back to the beasts rather than overcome man? What is ape to man? A laughing stock or painful embarrassment. And man shall be that to overman: a laughingstock or painful embarrassment. You have made your way from worm to man, and much in you is still worm. Once you were apes, and even now, too, man is more ape than any ape…. The overman is the meaning of the earth. Let your will say: the overman shall be the meaning of the earth…. Man is a rope, tied between beast and overman—a rope over an abyss … what is great in man is that he is a bridge and not an end.”

H. G. Wells said it far more beautifully:

“We look back through countless millions of years and see the great will to live struggling out of the intertidal slime, struggling from shape to shape and from power to power, crawling and then walking confidently upon the land, struggling generation after generation to master the air, creeping down the darkness of the deep; we see it turn upon itself in rage and hunger and reshape itself anew, we watch it draw nearer and more akin to us, expanding, elaborating itself, pursuing its relentless inconceivable purpose, until at last it reaches us and its being beats through our brains and arteries…It is possible to believe that all the past is but the beginning of a beginning, and that all that is and has been is but the twilight of the dawn. It is possible to believe that all that the human mind has accomplished is but the dream before the awakening; out of our lineage, minds will spring that will reach back to us in our littleness to know us better than we know ourselves. A day will come, one day in the unending succession of days, when beings, beings who are now latent in our thoughts and hidden in our loins, shall stand upon this earth as one stands upon a footstool, and shall laugh and reach out their hands amidst the stars.”

But Wells spoke of not of achieving that greatness personally, but rather of the species achieving it  – of our descendants achieving it.

To want it, to need it, to ache for it personally – that is a rare thing. It is the motive force that has driven biological evolution – and it is the motive force that has driven every human innovation and every human conquest – for good or evil.

Recently, a friend of mine asked, in wonder, why I was preparing for the contingency that technological civilization might collapse. “There would be no cryonics if that happened.” he noted, correctly.

“Yes, I know.” I replied.

“And it would be really horrible. A terrible, terrible undoing of the world.” he added.

“Yes, yes it would.” I agreed.

“Then why on earth would you want to be around to see that?”

“I can’t imagine missing the last act! I mean, honestly, I’ve had the chance to read up on all that happened before, I’ve trotted all over the planet, read the thoughts of the best minds of every known culture and civilization, and you propose I should wimp out and miss the denouement? I’m plenty savvy enough to keep redundant assets for a quick and painless exit at should I find myself in unbearable agony and no hope of survival. However, absent that, I can’t even conceive of betraying the intense curiosity I’d have about any apocalypse, even if my own survival were impossible.”

Frankel comes close to summing up my feelings on this matter when he says:  ”Man is that being who invented the gas chambers of Auschwitz; however, he is also that being who entered those gas chambers upright, with the Lord’s Prayer or the Shema Yisrael on his lips.” There is an implied qualification not present in Frankel’s quote:  “Man at his best is that…” The cryonicist is thus that being who chooses life, inquiry, knowledge and understanding of the universe as his personal and moral imperatives. He chooses to feel and to be these things – not just to think about them, or talk about them. He chooses action over contemplation, life over death.

The origins of that choice? Well, that is still a mystery, but one which, in the fullness of time, may we may hope to unravel.

Left Ventricle

Figure 43: The myofibrils of each cardiac muscle cell are branched and contain a single nucleus. The branches interlock with those of adjacent fibers by adherens junctions which act to prevent scission of the cardiomycytes during the high-shear, forceful contractions of the heart. The muscle is richly supplied with mitochondria which are largely confined to the spaces between the fibrils. The fibrils are covered with a membrane, the Sarcolemma, which is frequently invaginated to form the Transverse tubules. These invaginations of the plasma membrane or sarcolemma, are called transverse tubules and they reach deep into the myofibrils and  bring the action potential deep into the fibers. Specialized intercellular junctions, the Intercalated discs, facilitate rapid transmission of the electrical signals which initiate myocyte contraction. The myofibrils are formed by myosin and actin fibers aligned in a distinct pattern which is visible under light microscopy as the A-, H- and I- bands.

      Yajima stain was used to prepare the Control (Figure 44), FGP  and FIG cardiac tissue for light microscopy. The FGP cardiac muscle showed increased interstitial space, probably indicative of interstitial edema. In many areas the sarcolemma appeared to be separated from the cytoplasm of the myocyte and, occasionally, appeared to have disintegrated into debris in the interstitial spaces (Figure 45). The myofilaments appeared maximally relaxed with widened I-bands . The mitochondria were grossly swollen and contained numerous amorphous matrix densities. The sarcolemma was fragmented beneath an intact basement membrane and there was increased space between the capillary endothelium/basement membrane and intact areas of the sarcolemma of the cardiomyocytes. The cell nuclei  were unremarkable.

Figure 44: Control-1, Left  Ventricle, Yajima, 100x. Control cardiac muscle demonstrated crisp, well defined membranes and the normal density and pattern of myofibril structure. Capillary endothelium appeared intact and the capillary basement membrane was well anchored to adjacent myocytes and appeared intact.

Figure 45: FGP-1 Left Ventricle, Yajima, 100x. In the FGP animals the myocardium exhibited increased interstitial space (IIS) as well as the presence of debris in the IIS which appeared to be disrupted sarcolemma (yellow arrows). The capillary basement membrane was often observed to be separated from the sarcolemma of the adjacent myocytes and endothelial cell nuclei were sometimes observed devoid of plasma membranes or cytoplasm (red arrow).The occasional naked myocyte nucleus could also be observed (green arrow).

The same changes were also present in the FIG group with the added presence of a “ragged” or rough appearance of the myofibrils where they were silhouetted against interstitial space (Figure 46). There also appeared to be holes or spaces, possibly as a result of edema, in the fabric of the myofibrils that were not present in the myocardium of either the control, or the FGP animals.

Most surprising was the general absence of contraction band necrosis in the FIG group, possibly as a consequence of the protective effect of reasonably prompt post-cardiac arrest refrigeration. No microscopic evidence of fracturing, either gross or microscopic, was noted in the myocardium of either the FGP, or  the FIG groups.

Figure 46: FIG-2 Left Ventricle, Yajima, 100x. Separation and fragmentation of the sarcolemma were observed in the FIG myocardium to a greater extent than that seen the in myocardium from the FGP animals (yellow arrow). Additionally, the fibers of myofibrils had a more ragged appearance and consistently displayed open spaces in the bands which were not seen in the myocardium of either the Control or the FGP animals (red arrows).

 Figure 47: The myofibrils of both the FGP and FIG animals appeared maximally relaxed with a marked increase in the thickness of the I-band. Intact red blood cells (RBCs) were observed in the FIG animals and represent incomplete blood washout (red cell trapping) despite perfusion with large volumes of washout, cryoprotectant and fixative solution (~8-10 L) over a time course of ~140 minutes of perfusion.

Cerebral Cortex

 Figure 48: The cerebral cortex consists of six distinct layers, beginning with the first layer, the Molecular Layer (Stratum zonale), which consists of finely branched medullated and non-medullated nerve fibers. The molecular layer is largely devoid of neuronal cell bodies. Those neuronal cell bodies which are present are the cells of Cajal which possess irregular cell bodies and typically have four or five  dendrite that terminate within the molecular layer and a long nerve fiber process, or neuraxon, which runs parallel to the surface of the cortical convolutions.

 The second layer of the cortex consists of a layer of small Pyramidal cells with the apices of the pyramids being directed towards the surface of the cortex. The apex of the small Pyramidal cells terminates in a dendron, which reaches into the molecular layer, giving off several collateral horizontal branches. The final branches in the molecular layer take a direction parallel to the surface. Smaller dendrites arise from the lateral and basal surfaces of these cells, but do not extend far from the body of the cell. The neuronal axon (neuraxon) always arises from the base of the small Pyramidal cells and passes towards the central white matter, thus forming one of the nerve-fibers of the white matter. In its path, the neuraxon gives off a number of collaterals at right angles, which are distributed to the adjacent grey matter.

The third cortical layer consists of Pyramidal neurons which are characterized by the presence of cells of the same type as those of the preceding layer, but of a larger size. The nerve-fiber process becomes a medullated  fiber of the white matter.

 The fourth layer is comprised of  Polymorphous neurons which  are irregular in outline and give off several dendrites which branch into the surrounding grey matter. The neuraxons of the Polymorphous neurons give off a number of collaterals, and then become a nerve-fiber of the central white matter. Scattered through these three layers are the cells of Golgi, whose neuraxon divides immediately with the divisions terminating in the immediate vicinity of the Polymorphous neuron cell-bodies. Some cells are also found in which the neuraxon, instead of extending into the white matter of the brain, passes towards the surface of the cortex; these are called cells of Martinotti.

 The fifth cortical layer contains the largest pyramidal neurons which send outputs to the brain stem and spinal cord and comprise the the pyramidal tract. Layer 5 is particularly well-developed in the motor cortex.

 Layer 6 consists of pyramidal neurons and neurons with spindle-shaped cell bodies. Most cortical outputs leading to the thalamus originate in layer 6, whereas most outputs to other subcortical nuclei originate in layer 5.

The cortical blood supply is via the pia mater which overlies the cerebral hemispheres.

Bodian stain was used to prepare the control, FGP, and FIG brain tissue  samples for light microscopy. Three striking changes were apparent in FGP cerebral cortex histology: 1) marked  dehydration of both cells and cell nuclei, 2) the presence of  tears or cuts at intervals of 10 to 30 microns throughout the tissue on a variable basis (some areas were spared while others were heavily lesioned), and 3) the increased presence (over Control) of irregular, empty spaces in the neuropil as well as the occasional presence of large peri-capillary spaces (Figures 54,56, and 57). These  changes were fairly uniform throughout both the molecular layer and the second layer of the cerebral cortex. Changes in the white matter paralleled those in the cortex, with the notable exception that dehydration appeared to be more pronounced (Figure 55).

Other than the  above changes, both gray and white matter histology appeared remarkably intact, and only careful inspection could distinguish it  from control (Figures 52, 58, 59 and 60). The  neuropil appeared normal (aside from the aforementioned holes and tears) and many long  axons and collaterals could be observed traversing the field. Cell membranes appeared crisp, and apart from appearing dehydrated, neuronal architecture  appeared comparable to control. Similarly, staining was comparable to that observed in Control  cerebral  cortex. Cell-to-cell connections appeared largely intact.

The histological appearance of FIG brain differed from that  of FGP animals in that ischemic changes such as the presence of pyknotic and fractured nuclei were much in evidence and cavities and tears in the neuropil appeared somewhat more frequently. The white matter of the FIG animals presented a macerated appearance, in addition to exhibiting the rips or tears observed in the white matter of the FGP brains (Figure 61).

Both FGP and FIG brains  presented occasional  evidence of microscopic fractures.

Figure 49: Control-1, 1st (molecular) cell layer, cerebral cortex, Bodian, 40x. Cells of Cajal (N) and a dense weave of axons (A) are visible. The tissue is perforated by numerous capillaries (C) and a  small venue containing many red blood cells (RBCs).

Figure 50: Control-1, 2nd cell layer, cerebral cortex, Bodian, 40x, showing a pyramidal neuron (N, lower left) multiple capillaries (C) and the interwoven connections of dendrites that comprise the neuropil.

Figure 51: Control-1, white matter, cerebral cortex, Bodian, 40x. Myelinated axons (MA) appear both in cross section (yellow arrows) and laterally (green arrows). Unmyelinated axons are present inside the black circle. Glial cell nuclei (GN) are scattered throughout the tissue.

 Figure 52: FGP-1, Cerebral Cortex, 1st cell layer, Bodian, 40x. Two large capillaries (LC) are present, one with a red blood cell present (right). Neurons (N, cells of Cajal) are present in normal density and the neuropil appears intact. This section appears indistinguishable from that of the Control animal.

Figure 53: FGP-1, Cerebral Cortex, 2nd cell layer, Bodian, 40x. This area of FGP cerebral cortex shows injury typical of that seen in both FGP and FIG animals. There are a number of large tears in the neuropil (red arrows) approximately 10 to 30 microns across. A pyramidal neuron is present in the lower left of the micrograph and it appears somewhat dehydrated. There are a number of naked glial cell nuclei (yellow arrows), as well some nuclei with what appears to adherent cytoplasm visible at the margins of the tears in the neuropil.  

Figure 54: FGP-1, Cerebral Cortex, 2nd cell layer, Bodian, 40x. In this area of the 2nd layer of the cerebral cortex the neuropil presents a somewhat “moth eaten” appearance, with numerous tears and vacuoles in evidence (red arrows). One large tear appears to be a pericapillary ice hole (yellow arrow).

Figure 55: FGP-3, Cerebral Cortex, white matter, Bodian, 100x. There are numerous open spaces in the white matter that appear to be ice holes (red arrows). The density of the tissue appears markedly increased over that of the Control white matter, possibly as a result of glycerol-induced dehydration. This apparent dehydration is also evident in the increased density of the axoplasm seen in the myelinated axons (green arrows).

Figure 56: FIG-3, Cerebral Cortex, 1st cell layer, Bodian, 40x. Extraordinarily normal appearing Molecular layer of the FIG cerebral cortex. The neuropil appears intact with the exception of what appear to be scattered tears or ice holes (red arrows).

Figure 57: FIG-2, Cerebral Cortex, 1st cell layer, Bodian, 40x. Large tears are evident (red arrows) and naked glial cell nuclei and fragmented cytoplasm are apparent (nn). Several intact capillaries are in evidence (C) as well as what appears to be two capillaries that have been separated from the neuropil and appear largely surrounded by open (pericapillary) space (green arrows). A mass of debris appears to occupy some of the luminal space of what appears to have been a capillary (Cd).

Figure 58: FIG-2, Cerebral Cortex, 2nd cell layer, Bodian, 40x. Remarkably intact neuropil with several capillaries, including several capillaries sectioned oblique to the plane of the tissue (OC). A neuron (N) with what appears to be a crisp plasma membrane is present at the upper right of the micrograph.

Figure 59: FIG-2, Cerebral Cortex, 2nd cell layer, Bodian, 40x.Normal appearing cerebral cortex in an FIG animal. There are multiple intact neurons with normal appearing dendrites (D) and axons (A). An intact large capillary (LC) is present and appears free of red cells.

Figure 60: FIG-2, Cerebral Cortex, 2nd cell layer, neuropil, Bodian, 100x. Normal appearing layer 2 of the cerebral cortex with intact neurons (N), axons (A), and neuropil. A capillary (C)with intact endothelial cells and an endothelial cell nucleus (EN) is also visible (left, center).

Figure 61: FIG-2, Cerebral Cortex, white matter, Bodian, 40x. Severely injured white matter typical of that seen in FIG animals. The tissue presents a macerated appearance (black circles) with numerous rips and tears, possibly as a result of ice formation (red arrows). The capillaries (C) are separated from the tissue parenchyma (yellow arrow) and what appears to be a naked endothelial cell nuclei projected into the intraluminal space of one capillary (green arrow).

END OF PART 3

Histology was evaluated in two animals each from the FIG and FIGP groups, and in one control animal.  Only brain histology was evaluated in the straight-frozen control animal.

Liver

      The histological appearance of the liver in all three groups  of animals was  one  of  profound injury.  Even in the FGP group, the cellular integrity of the liver appeared grossly disrupted.  In liver tissue prepared using Yajima stain, the sinusoids and spaces of Disse were filled with flocculent debris, and it was often  difficult or impossible to  discern cell membranes (Figures 30-32). The collagenous  supporting structures of the bile canaliculi were in evidence and the nuclei of the hepatocytes appeared to have survived with few alterations evident at the light level, although frequent pyknotic nuclei were noted in the FIGP group (Figures 31 & 34).  Indeed, the nuclei often appeared to be floating in a sea of amorphous material (Figure 34).  Not surprisingly, the density of  staining of the cytoplasmic material was noticeably reduced over that  of  the fixative-perfused control. Few intact capillaries were noted.

FGP  liver  tissue prepared with PAS stain  exhibited  a  similar degree  of disruption (Figure 32).  However, quite remarkably, the borders of  the hepatocytes  were defined by a clear margin between  glycogen granule containing cytoplasm  and non-glycogen containing membrane or other material (membrane debris?) which failed to stain with Yajima due to gross physical disruption, or altered tissue chemistry (Figure 35).

Figure 28: Control-1 Liver, Yajima, 100x. Liver sections from the Control animal demonstrated normal morphology as can be seen in the image above.

Figure 29: Control-1 Liver, PAS, 100x. Liver sections were prepared with both Yajima and PAS stain in order to allow visualization of structures that neither stain discloses alone; in this case, most importantly, the presence or glycogen granules in the hepatocytes of the Control animal. Note the presence of normal intralobular architecture with crisp cell membranes in evidence, normal appearing sinusoid spaces, and residual sinusoidal red blood cells (RBCs) not washed out during fixative perfusion.

Figure 30: FGP-1 Liver, Yajima, 100x. The livers of FGP animals demonstrated extensive histological disruption. The sinusoids were all but obliterated and appeared filled with debris (ds) and the cytoplasm was extensively vacuolated (v). 

Figure 31: FIG-2 Liver, Yajima, 100x. As was the case with the FGP animals, the sinusoids were barely discernable and appeared filled with cellular debris (cd). In addition to extensive cytoplasmic (cv) and nuclear vacuolization (nv), pyknotic nuclei (pn) were also present. Cell membranes were difficult to discern and in many areas, frank cell lysis appears to have occurred with flocculent cellular debris (cd) appearing to fill the sinusoids.

Figure 32: FGP-1, Liver, PAS, 100x. The intensely red-stained granules present in the cytoplasm of the hepatocytes are glycogen deposits selectively stained by PAS. There is extensive cytoplasmic (cv) and nuclear vacuolization (nv) and the sinusoids appear filled with flocculent cellular debris (d). Indeed, it is only possible to discern the outlines of the original individual hepatocytes from the pattern of the intracellular glycogen granules disclosed by the PAS stain.

Figure 33: FIG-2, Liver, Yajima, 100x, well preserved area. While the bulk of the hepatic parenchyma exhibited the severe injury seen in Figures 30-32, there were frequently observed islands of comparatively well preserved tissue visible in both the FGP and FIGP sections suggesting that freezing injury is occurring non-homogenously.

Figure 34: FIG-2, Liver, PAS, 100x, necrotic area. There were patchy areas of frank necrosis visible in the livers of the FIGP animals that were not present in the livers of the FGP animals. This area, adjacent to  a central vein, shows extensive cell lysis with heavy vacuolization of the cytoplasm (v) and many pyknotic nuclei (pn) in evidence.

Figure 35: FIG-2, Liver, PAS, 100x. Note the presence of a few scattered glycogen granules (GG). Interestingly, in this comparatively well preserved area of FIGP liver it is possible to see some remaining deposits of glycogen that were not consumed during the long post-arrest ischemic interval. The absence of pyknotic nuclei and the relative absence of large intracellular vacuoles is also remarkable.

 Kidney

Figure 36: The functional unit of the kidney is the nephron, consisting of the glomerulus and the uriniferous tubule ( the renal corpuscle: a).The capillary tuft of the nephron, the glomerulus, is enclosed within a double cell layered structure; Bowman’s capsule. Bowman’s capsule and the capillary tuft it encloses comprise the glomerulus. Bowman’s capsule and the glomerular capillary tuft constitute the renal (or Malpighian) corpuscle (b).

PAS  stain  was used to prepare the control, FGP and  FIGP  renal tissue for light microscopy.  The histological appearance of FGP renal tissue was surprisingly good (Figures 329, 40 & 41).  The glomeruli and tubules  appeared grossly intact  and stain uptake was normal.  However,  a  number  of alterations  from  the appearance of the control were  apparent.  The capillary tuft of the glomeruli appeared swollen and the normal  space between the capillary tuft and Bowman’s capsule was absent.  There was also marked interstitial edema, and marked cellular edema as evidenced by the obliteration of the tubule lumen by cellular edema.

By contrast, the renal cortex of the FIGP animals, when  compared to  either  the control or the FGP group, showed a  profound  loss  of detail, absent intercellular space, and altered staining (Figures 40 & 42). The  tissue appeared frankly necrotic, with numerous pyknotic nuclei and  numerous large  vacuoles  which peppered the cells.  One  striking  difference between FGP and FIGP renal cortex was that the capillaries, which were largely  obliterated in the FGP animals, were consistently  spared  in the FIGP animals. Indeed, the only extracellular space in evidence in this  preparation was the narrowed lumen of the  capillaries,  grossly reduced in size apparently as a consequence of cellular edema.

Both ischemic and non-ischemic sections showed occasional evidence of  fracturing, with fractures crossing and severing tubule cells  and glomeruli (Figure 41).

Figure 37: Control, Renal Cortex, PAS 40x. Three glumeruli are present (G) adjacent to crisp, well defined proximal (P) and distal (D) convoluted tubules. The intertubular capillaries (C) show normal diameter with lumens free of red cells or debris. There is normal capsular space between Bowman’s capsule (BC, yellow arrows) and the glomerular capillary tuft and vascular pole (VP) are also normal in appearance.

Figure 38: Control-1, PAS 40x. Collecting ducts (CD), distal tubules (D) and a glomerulus  (G) are present in 6this micrograph of renal apical column. At right, a glomerulus is present with normal Bowman’s space (BS) and the macula densa (MD) in evidence.

Figure 39: FGP-1, Renal Cortex, PAS, 40x. The intertubular space (ITS) is great expanded and the tubule cells are heavily vacoulated (V) and lack definition. The intratubular space (IS) is no longer in evidence and the architecture of the glomerluar capillary tuft (GT) is radically altered and there is an absence of the normal architecture of Bowman’s space (yellow arrows). The intertubular capillaries appear to have been reduced to debris (D) visible in the intertubular spaces.

 Figure 40: FIG-2 Renal Cortex, PAS, 40x. There is massive cellular edema present with almost complete obliteration of Bowman’s space. The tubule (T) lumens are no longer visible and the tubule cells are extensively vacoulated with many pyknotic nuceli in evidence. Individual tubular cell membranes are impossible to resolve. The afferent glomerular arteriole (AA) appears intact (red arrow).

Figure 41: FIG-2 Renal Cortex, fracture present (arrows), PAS, 40x. Two renal tubules, possibly a proximal and distal convoluted tubule (T) are dissected by a fracture as is the macula densa (MD) of the glomerulus (G). Remarkably, there is still a small amount of intertubular space present in this micrograph.

Figure 42: FIG-2 Renal Cortex, PAS 40x. vacuolization (black arrows) and extensive vacuolization (blue arrows) accompanied by necrotic changes, such as the frequent presence of pyknotic nuclei (red arrows).

END OF PART 2