X-Message-Number: 33155 From: Date: Tue, 28 Dec 2010 17:12:39 EST Subject: Scoring Cases Content-Language: en Gerald, These are very good questions and are certainly not the kind of questions asked by people who have been recruited into cryonics over the past 15 years, or so. Could you tell me more about yourself, either here on CryoNet, or via personal communication? References: <_ (mailto:) > From: Gerald Monroe <_ (mailto:) > Date: Tue, 28 Dec 2010 06:04:06 -0600 Subject: Re: CryoNet #33145 - #33149 --0015175ce0860fa1dc049877414c >>I'm still stuck on the following. If we cool the patient down while preventing hypoxia, and then do not leave them 'liquid' and in a hypoxic state longer than proven guidelines for possible recovery, freezing the brain solid and then chilling it to the point that molecular motion almost ceases, what could go wrong? What physical structure COULD neurons store information in that would not be retained in this manner? The functional systems of the brain may contain many mysteries, but it's still an object made of ordinary matter.>> Yes, the brain is made up of ordinary matter, and for the record, no, I am not a mystic: I think it almost certainly the case that memory, personality and identity can be fully explained on the basis of the physical structure of the brain/body. And if we had a way to render those structures into a solid state, devoid of meaningful biophysical change, then we would indeed be preserving the individual in a viable state - and if we could reverse that process without harm, then we would have suspended animation and survival of the treated individual. But there's the rub, we do NOT have such a method at hand. When you write: "freezing the brain solid and then chilling it to the point that molecular motion almost ceases, what could go wrong?" you put your finger on the kernel of the problem. Currently, we have two ways to achieve durable (indefinite) biopreservation, and those are freezing and vitrification. Both of these processes cause enormous perturbation of brain structure on both the tissue and the molecular level. Currently, we believe that vitrification causes less perturbation to the structures we think are the best candidates for encoding memory and personal identity, and so that is why it now considered the "best' treatment. However, there is substantial evidence that most patients who are being "vitrified' are in fact only partially vitrifying and in many cases may be freezing - and freezing under conditions that may be far worse than had they been frozen using conventional methods of cryoprotection and slow cooling. But before I discuss the biophysical changes that may attend vitrification, I want to discuss freezing injury, in part because there is some overlap between it and freezing in terms of the injury inflicted. WHAT COULD GO WRONG: It is probably no accident that a large fraction of the people recruited to cryonics since its inception have been engineers, mathematicians, computer scientists, programmers, and, in general, physical science types. I believe one reason for this is that there is a fundamental difference in the way biological machines and electromechanical machines are structured and operate. Almost all electromechanical systems may be fairly described as solid state - even those in existence before the advent of electronics, and before the advent of the transistor. By solid state I mean that virtually all their components are, literally, solid at their normal operating temperatures. A consequence of this is that I can take a 21st Century Android phone or a 17th century clock, and whack them with a sledgehammer and the end result would broadly be the same: I'd have a bunch of solid pieces of varying sizes and shapes that just sat there - and of course, neither the phone nor the clock would work any longer. But, all the pieces would still be there and they would retain their individuality and unique identity. And such will be the case indefinitely, as long as they are protected from the elements. Biological systems are NOT solid state devices, and they operate in very different ways. The core of biological systems is the membrane; and membranes in living systems are not just passive walls or "compartment makers': they are the engines of chemistry and action in living systems. They have enormous complexity and they derive a great deal of their unique ability to function as living systems from their liquidity and plasticity. If I were to reach for a meaningful physical analogy in the everyday macro-world, the analogy would be that of soap bubbles. Cell membranes are very much like soap bubbles, and they behave in broadly similar ways when stressed. If you osmotically stress a cell by shrinking or swelling it too much, it does not behave like a glass sphere and shatter into discrete pieces which can be collected and reassembled. Rather it buds and blebs and behaves like what it is, a liquid. And if you stress it enough, it simply comes apart into little droplets and into smaller "cells,' vesicles that have formed from the original membrane. Before such dramatic changes occur, the structure of the membrane can undergo reorganization in many ways, and the proteins embedded in the membrane may be rearranged as well. This is true not just for the plasma membrane that encases the cell, but also for the membranes that comprise the cellular organelles. In fact, it is rearrangement of mitochondrial membrane structure that underlies some of the damage that occurs in ischemia. Freezing causes enormous mechanical stress to the plasma membrane, and to organelle membranes, and some of the response to this stress is to radically alter membrane structure. In the worst case, the cell membrane(s) disappear as the structures they were, and reappear as new structures; droplets of membrane material, brand new micro-cells and so on. And they shed structures that were embedded or enclosed in them; thus the debris fields seen in frozen thawed tissues. Biological systems are NOT solid state devices and if you damage them badly enough they do not sit around as discrete, broken pieces waiting to have their pre-injury, functioning structure inferred from the broken pieces. And it is important to understand that some of this "remorphing' goes on during the freezing process as a consequence of the enormous osmotic and mechanical stresses imposed by ice formation. Further, there are significant changes to membrane structure, such crystallization of the lipids that occur solely as a result of cooling, and completely independent of freezing. To return to the Android phone analogy, it would be as if the Android were made up of liquids encased in soap bubbles and you squashed it. Imagine a soap bubble with an exquisitely detailed painting embedded into its surface. A painting made up of millions of tiny pixels comprised of colored nanoparticles. If you burst the bubble, some of the bubble wall material will return to a simpler, all-fluid state, and some of it may reform into new bubbles. But in any event, the painting is gone and what's more, it is not obvious that it can be inferred from the puddle of particles in liquid and the new bubbles that result. So that is one thing that can go wrong. I think it likely that procedural memory is encoded in hard connections between neurons. But it is possible that declarative memory relies on a different mechanism; perhaps changes in the character of the synapses, neuronal cell membranes, number or distribution of vesicles or other membrane-based structures, or discrete changes in the chemistry of the neuronal membranes. BOTH freezing and vitrification have the potential to disrupt those kinds of structures in ways that would leave them uninferrable. Vitrification may do this by the expedient of altering membrane structure irreversibly by dehydration, or by changing the molecular structure of the membranes or membrane components by directly perturbing their structure. Vitrification solution is NOT water, and water is critical to the structure of many of the molecules inside cells. Indeed, a good part of the science behind designing tolerable vitrification solutions is to make them behave as much like water as possible - while at the same time behaving as good glass forming agents when cooled. As I said before, we simply don't how memories are encoded in the brain and far more profoundly, we do not have a solid proven theory of what comprises human identity - leaving particular structures out of it. This is one of many reasons why we should be striving mightily to achieve fully reversible suspended animation; because we JUST DON'T KNOW ENOUGH YET. >>Storage at near 0 C during transport might be a big mistake. You could easily be correct.>> >>But it we were hypothetically presenting the science of cryonics to an unbiased review board and we say : step ONE patient's brain is revivable,therefore it contains the long term memory data. Step TWO : a short time after step ONE, we have frozen the brain and the larger molecules are completely unable to go anywhere. They have not budged from where they were located in Step ONE. Step THREE is of course the brain after a century in liquid nitrogen...hopefully almost the same as steps 1 and 2.>> This is all fine and dandy as long as you can posit that the molecules have not budged from where they were whist in a fully functional state. But you cannot do that, and neither can anyone else. >>It seems like it ought to be possible to write equations describing the information state of the brain in step one followed by step two, and mathematically PROVE that a negligible amount of information has been lost in the transition. We would need to know nothing at all about memory storage, except that it is performed by large durable molecules above a certain number of daltons.>> Yes, that is correct: now, define "negligible' and prove that the molecular structure is essentially unperturbed. Do that, and your statement stands as correct. >>This is under ideal circumstances: patient has good standby care by a competent medical team, and chooses to be suspended a short drive from the cryonics lab. One way to ensure this would be to have the patient on an active life support machine that the patient could order switched off, causing the patient to legally die when the team is ready. That would be a frightening moment, and one that I hope all of us here have a chance to experience (assuming a method for keeping the brain alive in it's current form is not developed in the next 50-80 years).>> Well, it might be frightening to you, but having seen countless dying patients in this condition, and knowing the distress and hopelessness they feel (after all, many know they are DYING), I would not find the "switch off' of "life support' frightening at all - indeed it would be the prospect of CONTINUED life support that might render my brain into an unrecoverable state that I would find - not frightening - but terrifying. >>Your clinical examples aren't very illustrative because you're talking about edema for a period of days killing billions of neurons, and now the patient cannot retrieve their memories. Are the memories gone? Did neurons involved in the process of searching and retrieving declarative memory data get destroyed? Who knows, but the patient has been allowed to fester in a hospital bed for weeks while the damaged neurons are eaten by macrophages, and none of the damage has been repaired or the missing cells replaced. If I go attack your desktop computer with a soldering iron and short a few hundred randomly chosen circuits, you would not necessarily conclude that the data on your computer was destroyed past any method of recovery. Especially if your computer stored it's data in hundreds of distributed storage chips scattered all across the mainboard.>> I think my clinical example of cerebral edema and declarative memoery loss is very much on point because it COULD imply that it is NOT the death of brain cells that cause's memory loss, but rather some alteration in membrane structure as a result of edema. In fact, we can be sure that neuronal cell death, either from apoptosis or necrosis is NOT the cause of such memory loss. These patient do not experience global loss of neurons and the areas where they suffer the most neuron loss, the prefrontal cortex, is not generally associated with memory storage or retrieval. Nor are there visible losses in the white matter connections in the inflow/outflow tracts to the hippocampus - nor is the hippocampus catastrophically injured (e.g. by MRI imaging). Certainly it is possible that they have lost access to their memories, rather than the memories themselves. But this hypothesis fails to explain why, after they make a recovery from the acute injury, they can form, store and retrieve new declarative memories, but still not access the ones create prior to the trauma? Thus, there is much we don't know. And again, BRAINS ARE NOT COMPUTER CHIPS ON A MAINBOARD ;-). And neurons are not like transistors in a microchip; that analogy holds only where they do non-unique tasks. It might be better to think of them as microscopic flash drives written on soap bubbles. Finally, the quality of cryopreservation most patients are now receiving is dismal and has, on average, deteriorated since 1990. Optimal pretty much is a thing of the past in cryonics anywhere in the world today. Mike Darwin Content-Type: text/html; charset="UTF-8" [ AUTOMATICALLY SKIPPING HTML ENCODING! ] Rate This Message: http://www.cryonet.org/cgi-bin/rate.cgi?msg=33155