28 replies to this topic

[Da55id]

Aubrey's recommendation is sound. Companies that specialize in tissue preservation via cryonics will do well. This will lead to greater and greater scalability and credibility. Boil a cup of tea - then you can think about the ocean.

[jonano]

in 2020, cryonics will be a hot market

[Da55id]

I think you will all be surprised - I think 5 years for tissue preservation is the outside limit for major commercialization

[bgwowk]

I think Aubrey is too optimistic about cryonics suddenly becoming popular, but I'd be happy to be proven wrong.

I'm most intrigued by cosmos' statement

However, as far as I'm aware cryonics has yet to demonstrate that it can preserve enough structure and information in the brain for future reanimation to be feasible.

That's a rather extraordinary statement given the level of structural preservation that's now been demonstrated under ideal conditions.

http://www.alcor.org...servation1.html

http://www.alcor.org...tml/annals.html

I'm left with two somewhat rhetorical questions.

1) What kind of data are required to make a good case that enough structure and information is being preserved for future reanimation to be feasible?

2) Will the public really care about such a demonstration?

There have been enormous strides in the last 15 years, even just the last two years, demonstrating excellent information preservation by cryonics under ideal conditions. It has not made one bit of difference in the public perception of cryonics. Public misunderstanding of cryonics runs so deep that showing better micrographs, better viability, or better electrical activity, while all very important to cryonicists, is going to make very little difference in public opinion. If after all the technical progess that's been made, PhD biologist fiction authors still think that crashing airplanes into cryonics labs to "free" cryonics patients by cremating them is heroic, cryonics is a LOOONG way from public acceptance.

----BrianW

Edited by bgwowk, 07 November 2005 - 10:23 PM.

[jonano]

You need to give the time to people to discover what cryonics is, they just discovered what`s nanotechnology, they begin to discover anti-aging with MPrize, cryonics will follow and I predict a hot market for cryonics in 2020.

[jonano]

With my web site I often get people on google from the word cryogenics, they search for human cryogenics, or nanotechnology cryogenics, I receive alot of hits from those terms. Like I said, it will take time before the meme go to our society. It will help more when organ preservations will be a reality with vitrification, people will know that we can store organs for a long time and they will think about the brains.

[bgwowk]

I agree with cosmos that definitive proof is still lacking, although I think it would be surprising in light of current knowledge if it turned out that insufficient information was preserved under ideal conditions. What makes me cynical about any revolution in public perception is that cryonics is probably 90% of the way to demonstrably reversible brain preservation, and yet none of the progress has been noticed. The whole concept of sending people into the far future seems too abstract for the public to comprehend no matter how good the theoretical foundation becomes.

---BrianW

[Da55id]

yep -

incredibility -> credibility in

[Da55id]

I agree with cosmos that definitive proof is still lacking, although I think it would be surprising in light of current knowledge if it turned out that insufficient information was preserved under ideal conditions.  What makes me cynical about any revolution in public perception is that cryonics is probably 90% of the way to demonstrably reversible brain preservation, and yet none of the progress has been noticed.  The whole concept of sending people into the far future seems too abstract for the public to comprehend no matter how good the theoretical foundation becomes.

Can't really blame people for this. Man was 90% of the way to flying when the otto cycle engine was invented. What made the difference was actual controlled flying via wing warping - even then it took several years for people to believe it actually happened - and of course it meant nothing in anyone's daily life (for at least 6 decades - not counting bombers). AND the Smithsonian institution did its best to kill it...inducing (arguably) one of the Wrights to commit suicide.

Only when people's children are saved via preserved organ transplants in significant numbers with coverage on Oprah and the morning shows will this enter the public consciousness...and that's likely to be soon.

[bgwowk]

prometheus wrote:

In a nutshell, studies of severe ischemia (oxygen deprivation) show that irreversible (reperfusion no longer enables recovery) damage to dendrite structures occurs within 10 minutes, apoptotic mechanisms commence within 2 hours (DNA fragmentation) and necrotic neuronal death within 6 hours (liquefaction). A computer analogy would be hard disk meltdown within 10 minutes, integrated circuit meltdown within 2 hours and motherboard meltdown within 6 hours. Assuming the progress of damage can be arrested at any point within that timeframe (as proposed by cryonics) then one has the mind-boggling task of seeking to undertake repairs.

Loss of dendrite structure in 10 minutes? Nonsense! I myself have participated in experiments in which dogs were recovered WITHOUT NEUROLOGICAL DEFICIT after 15 minutes of normothermic global ischemia using a combination of drugs and post-resuscitation hypothermia. Those experiments are summarized in the paper:

http://www.alcor.org...tml/annals.html

Here's a paper showing recovery without deficit in most animals after 13 minutes of normothermic circ arrest using a combination of hypertension, hemodilution, and post-resuscitation hypothermia:

http://www.ncbi.nlm....st_uids=2298837

Here's a paper showing recovery of a cat after ONE HOUR of normothermic ischemia, with only loss of hippocampal and straital tissue. (The CA1 region of the hippocampus is well-known as the most ischemia-sensentive part of the brain.) Even this loss is almost certainly apoptotic, meaning technological intervention in apoptotic processes could stop the loss from occuring at all.

Living neurons can be cultured as long as 4 hours

http://www.ncbi.nlm....ist_uids=313541

and even 8 hours after clinical death

http://www.ncbi.nlm....st_uids=9482451

More comprehesive reviews of cerebral ischemic injury as it pertains to cryonics can be found at

http://www.alcor.org...l/ischemic.html

in which can be found the passage

From a cryonics (i.e., information-theoretic perspective), it is important to point out that throughout even a 120-minute-period of normothermic cerebral ischemia, the appearance of the plasma membrane layers, including synapses and myelin sheaths, is only altered modestly. Indeed, the first ultrastructural changes associated with what is currently considered lethal cell injury are to the mitochondria and ribosomes, and these do not usually appear until after 30 minutes of GCI.

At least one study of post-mortem ultrastructural degradation has been conducted on a small number of human subjects [108]. The histological and ultrastructural changes experienced in patients with 25 to 85 minutes of GCI, and without extensive pre-mortem brain trauma or pre-mortem cerebral no-reflow of prolonged duration, closely parallel those observed in animal models of GCI: astrocytic edema, clumping of nuclear chromatin, disassociation of the polyribosomes, detachment of the ribosomes from the ER cisternae, and swelling of the mitochondria with the presence of flocculent densities. Stability of the lysosomes and conservation of the structure of the neuropil over this time-course are well documented.

There are further useful references in

http://www.alcor.org...ldsonBrief.html

http://www.alcor.org...orcryonics.html

Finally, and most importantly, all this is IRRELEVANT to cryonics done under ideal conditions with a standby team present. Under such conditions, blood circulation and oxygenation can often be restored within 5 minutes of cardiac arrest. Cooling then commences, and the patient experiences no further warm ischemia. To see what kind of preservation results from this, consider that all the micrographs in the paper

http://www.alcor.org...servation1.html

were obtained after a complete stabilization/freeze/thaw cryonics procedure on dogs in cardiac arrest using 1990s technology. The warm ischemic interval, and subsequent life support technology used, was the same as experienced by human cases under ideal conditions. Those micrographs are superb.

---BrianW

[bgwowk]

I'm glad we agree that warm ischemic injury is not inevitable in cryonics if intervention is sufficiently rapid following cardiac arrest. However this discussion is worth continuing since ~3/4 of cryonics cases are not performed under ideal conditions.

Surely you're familiar with the consequences of 5 minutes of cerebral hypoxia and know that permanent brain damage is inevitable.

This deep-seated belief is the crux of our communication problem. What is the origin of this 4-6 minute limit? Answer: If you take a brain that has experienced more than 4-6 minutes of warm ischemia, restore blood circulation, and provide just normal supportive care for the ensuing hours and days, you will end up with a brain that is damaged due to extensive cell loss, especially in the hippocampus. We both agree on that.

The key point is that damage and death are something that you end up with, and only if there are no post-resuscitation interventions. Cell loss is not acute. It is secondary in the hours and days that follow resuscitation.

Let's look at your references.

(2) Brain Res. 1992 Dec 11;598(1-2):87-97
Electron microscopic investigation of the cerebral cortex after cerebral ischemia and reperfusion in the gerbil.
Tomimoto H, Yanagihara T.

This study documents acute dendrite swelling (not destruction) after a few minutes of ischemia. It tells us nothing about whether any interventions can reverse the observed changes, only that problems get worse after blood circulation is restored under ordinary conditions. We both understand and agree on that.

(3) Acta Neuropathologica 1984 Volume 64, Number 4 319 - 332
The density and distribution of ischemic brain injury in the rat following 2–10 min of forebrain ischemia
L. Smith, R. N. Auer and B. K. Siesjö

The key sentence in this abstract is

Ischemia was produced by a combination of carotid clamping and hypotension, followed by 1 week recovery.

Of course. If you restore blood circulation after an ischemic insult and do nothing but wait, the brain ends up blasted. Ischemia is like setting a timer on an explosive charge. That doesn't mean interventions can't defuse the bomb.

(4) Stroke. 1999 Mar;30(3):662-8.
Continuing postischemic neuronal death in CA1: influence of ischemia duration and cytoprotective doses of NBQX and SNX-111 in rats.
Colbourne F, Li H, Buchan AM, Clemens JA.

This one powerfully supports the point I'm trying to make. From the abstract

BACKGROUND AND PURPOSE: Transient forebrain ischemia results in a 24- to 72-hour delayed loss of CA1 neurons.... RESULTS: CA1 damage was not detected at 24 hours. Thirty minutes of ischemia produced 47% and 84% CA1 damage at 2 and 3 days, respectively.

Like I said, ischemia sets the charge, the blast happens hours after blood circulation is restored.

You stomped on the ANYAS paper I cited, and with good reason. Until the principal investigators properly write up the experiments anecdotally reported in that paper, they will remain a historical footnote no better than "personal communications". I only mentioned them because I helped with a couple of those experiments, and one of the surviving animals is still a healthy, normal pet that lives a couple of blocks from where I write this.

You did not comment on the Peter Safar paper, which fully documents recovery of dogs with an OPC score of 1 (neurologically normal) after 13 minutes of normothermic ischemia using a multi-modal approach to prevent no-reflow. The Safar Center in Pittsburgh is famous for this work (documented in many papers), and the whole approach of post-resuscitation hypothermia to "defuse" the ischemia time bomb is a hot area in critical care medicine right now.

This discussion reminds me of cryobiologist Ken Storey's famous quote about cryonics

What happens is, every single cell in the organism breaks. Everything is crushed, and it is not just a tiny little bit of damage, it is not damage like a hole in a dike, it's damage like complete pulverization and destruction. Not just the destruction of cells, but also the information contained in them. The DNA is broken up, destroyed, and oxidized. There is not a single salvageable piece of anything that is molecular inside those things [Alcor patients].

When I contacted him privately to ask about that quote, which is dramatically contradicted by electron micrographic evidence, he responded that present cryopreservation methods will induce apoptosis and necrosis so that revival attempts would inevitably lead to cellular dissolution. In other words, if you take a cryopreserved person and just perfuse warm blood through them for a few days, they'll turn to mush. Duh!

---BrianW

[bgwowk]

Again, ischemia sets the time bomb ticking, but it is restoration of warm blood flow that actually blows the bomb hours later. Of course just leaving a brain sitting in a warm ischemic state (clinical death) long enough will also destroy brain structure as seen by electron microscopy. But that also requires many hours.

It's interesting that the three most clinically effective interventions for treating warm ischemic injury, hypothermia (to reduce inflammation and brain swelling), hypertension (high blood pressure to force blood through constricted blood vessels), and hemodilution (to decrease blood cell density), all mitigate the notorious no-reflow effect. In other words, individual brain cells are capable of recovering after much longer than 4-6 minutes of ischemia, but in a whole brain they end up getting killed by a few minutes of ischemia mostly because blood vessels supplying them become blocked during resuscitation.

There are strong parallels between aging intervention and treatment of cerebral ischemic injury. In both cases there is a conventional wisdom that borders on dogma (animals cannot live beyond their species maximum life span, 5 minutes of warm ischemia causes irreversible brain damage). In both cases there is a simple intevention that smashes the dogma (calorie restriction, post-resuscitation hypothermia). In both cases the philosophical significance of the invention is not appreciated, and people still talk about maximum life spans and ischemia survival limits as physical absolutes as though no interventions were possible.

There are particularly strong parallels between SENS and treatment of cerebral ischemic injury. In general concept, SENS says that aging can reversed by looking at the specific changes that happen during aging and finding tools to reverse them. In general concept, ischemic injury can also be reversed by studying specific changes caused by it, and using appropriate tools to reverse the changes during the resuscitation phase. The key is to look at aging and cerebral ischemic injury as physical problems to be solved, not mystical events.

Prometheus, please tell me if I'm making sense.

---BrianW

P.S. In case you missed it, please note my reply to the technical issues you raised in the message preceeding this one.

[bgwowk]

Sorry for the delayed reply. I was out of town.

You wrote:

Essentially you're suggesting that early neuron damage is reversible, provided circulation becomes adequately restored,

I would prefer to be more general and say, "provided certain interventions are made". Of course, the more severe the damage, the more radical the interventions will have to be until at some point the requisite information for repairs just isn't there anymore. For the very earliest damage, the simple intervention of post-resuscitation hypothermia seems to double ischemia tolerance time.

whereas I am saying that certain types of neuronal damage that occur from a 5 minute hypoxia cannot be rescued.

Which is certainly false, at least in terms of clinical outcome in whole animals when interventions such a post-resuscitation hypothermia, hemodilution, and hypertension are used.

You've underlined two sentences in the abstract. The second one you underlined is not relevant because it merely describes the consequences of prolonged post-ischemic reperfusion without intervention. (Rather like Ken Storey's famous characterization of the state cryonics patients would be in if warm blood circulation were restored for hours without any repair interventions!) The first underlined sentence describes processes (swelling, vacuolization, and microtubule disintegration) that are in fact reversible, even by natural mechanisms. Microtubule disinegration (depolymerization) followed by spontaneous reassembly is common in biology, such as occurs in reversible deep hypothermia.

The bottom line is that things don't suddenly go to heck in a handbasket after 5 minutes of cerebral ischemia. Ischemia lights the fuse, but the bomb blows hours later. Coincidentally, the home page of Imminst today carried the story

"We are able to rescue neurons [from the results of a stroke] at a time when most research suggests they are already dead. ... The USF study challenges the notion that nerve cells inevitably die quickly in the core region of the brain most severely deprived of oxygen and nutrients when a stroke hits. Instead, the researchers suggest, many nerve cells within ground zero of the attack, like those in mild to moderately damaged outlying areas, may succumb over several days through a slower, more orderly process known as apoptosis, or programmed cell death. ... This delayed death would permit more time to deliver neuron-sparing treatments than originally thought."

---BrianW

Edited by bgwowk, 15 November 2005 - 03:53 AM.

[bgwowk]

How do you reconcile the established clinical definition of death in light of your view on cerebral ischemia?

For a patient with DNR (do not resuscitate) order on their chart, legal death will be declared based on cardiopulmonary arrest. If a resuscitation attempt is being made, legal death will be declared when the treating physician "calls the code" after determining that the heart cannot be restarted. Sometimes patients who are successfully resuscitated will end up in a coma on life support, and may be declared brain dead days later. Those are the three basic ways people legally die, assuming that is your question.

Note that the criteria used are different in all three cases. The same physical state (e.g. 3 minutes of cardiac arrest) can be considered as either dead or alive depending on whether the patient has a DNR order. Death in medicine is not a rigorously defined biological state. Sometimes even conscious people are declared dead, such as when a doc calls the code on a patient who is being kept conscious by CPR (it happens).

Actually there is a fourth way you can be declared dead. If in a news report you hear the term "dead at the scene", it means that the victim has suffered trauma so severe that it's obvious to first responders that nothing can be done. I suppose there's a fifth way too, if we consider the legal process of declaring a missing person dead.

Every definition of death used in medicine today is essentially pragmatic, not biological. Death is a legal decision that further care is not appropriate given circumstances. That's all.

Here are some good quotes:

"Cardiac death isn't a diagnosis of death, it is a prognosis of death."

David Crippen, MD, FCCM
Department of Critical Care Medicine
University of Pittsburgh Medical Center

and

"The utility of the information-theoretic criterion of death to this case and this discussion is to point out that few if any patients pronounced dead by today’s physicians are in fact truly dead by any scientifically rigorous criteria."

The latter quote is from the latest issue of the medical journal Critical Care, which contains the article "Pro/con ethics debate: When is dead really dead?"

http://www.alcor.org...ry/html/dcd.htm

---BrianW

Edited by bgwowk, 16 November 2005 - 05:32 PM.

[gomez1]

I think Aubrey's recommendation plays an important role.Cryonics would be the good resource after 5 or 10 years.Thanks.
-----------------------
gomez

Edited by shepard, 18 January 2009 - 03:46 AM.
Removed spam URL in signature.

[Evolutionary]

Investing in cryonics is like investing in a technology that has a negligible probability of saving your life- it's like pascal wager's or winning the lottery, the chances of you being revived are negligible(at least to me now)-but the reward-the stakes- are extremely high.