X-Message-Number: 11685
Date: Thu, 6 May 1999 07:47:34 -0400
From: Mike Darwin <>
Subject: Cryonics: Yesterday's Technology Tomorrow

WARNING: The following is likely to be offensive to many of the persons who
subscribe to this list. If you do not wish to read or be exposed to
materials which could make you angry, defensive, or otherwise upset you,
please stop now. This post is also moderately technical, if you don't enjoy
reading about technical matters, this post probably isn't for you either.
I have not posted to Cryonet in a long time, and probably will not post to
it again for a long time, if ever. I am not a regular "reader" but I skim
Cryonet with some frequency, usually reading no further than the subject
line, or a line or two from a paragraph here or there. The principal reason
I continue to open the file when it is downloaded is that Doug Skrecky
occassionally posts things from the scientific literature which I find

I stopped participating in Cryonet and cryonics by and large for the
reasons Charles Platt cited when he unsubscribed with such "relish" awhile
back. My attitude is more easy going than tha.t.  I think people should
talk about what they want to in an un-moderated forum. (I will also say
that since Cryonet was started, I've come to realize via participation in
other un-moderated forums that un-moderated forums almost always decay or
fail in various ways.) Anarchy is another word for entropy.

When I quit posting to Cryonet and distanced myself from cryonics it was
for many comlex reasons, not all of which are accessible to examination by
me, let alone others not familiar with the history of cryonics in general,
or my 30+ years involvement with it. However, at the time I made the
decision to stop my public dialogue with the cryonics world, I made a
promise to myself that, when or _if_ a certain event ocurred, I would point
it out, on Cryonet, and in other appropriate venues in the cryonics

The last posting I show a record of to Cryonet was 03/11/97, I feel sure
Keith Lynch will correct me if there are later ones. I figured the odds
were pretty good I'd have to write this post, but I didn't know how long it
would take.

Then, on 04 May, 1999 the following post appeared:

>CryoNet - Tue 4 May 1999

> #11670: Nitric Oxide confirmed as a regulator for Cell Death [Olaf Henny]
>Message #11670
>Date: Mon, 03 May 1999 08:53:25 -0700
>From: Olaf Henny <>
>Subject: Nitric Oxide confirmed as a regulator for Cell Death

>I am re-posting below an article from Cryonet after obtaining Steve's
>permission.  I believe it will be of great interest in this group.


>Message #11641
>From: "Stephen Bogner, P.Eng." <>
>Subject: Nitric Oxide confirmed as a regulator for Cell Death
>Date: Thu, 29 Apr 1999 13:25:38 -0600
>Researchers at the Howard Hughes Medical Institute (HHMI) at Duke
University in collaboration with scientists at the Dana-Farber Cancer
Institute have
>now found that nitric oxide (NO), a well-studied molecule implicated in a
>host of communication pathways in and between cells, is also a switch that
>controls whether cells live or die.

>Stamler and his colleagues found that NO molecules occupy a critical site
>the enzyme caspase, a molecular "executioner" within human cells. When
>occupying this site, NO effectively plugs a communication pathway that
>activates caspase and triggers cell death.
>"We showed that nitric oxide sits on the site and keeps the enzyme
>inactive," said Stamler. "Conversely, the nitric oxide is removed in cells
>programmed to die. Simply put, if you block nitric oxide production within
>the cell, you make the cell more susceptible to cell death. And if you add
>it back, you prevent cell death."

>Apoptosis can be triggered through a biochemical chain of events known as
>the Fas pathway. When activated, the Fas pathway initiates a cascade of
>signals within the cell that ultimately turns on caspase. When NO occupies
>the site on caspase, however, the death message is blocked. Fas somehow
>manages to pop the nitric oxide off the cells that are programmed to die.

> "We'd like to think modulation of the nitric oxide system can be used for
>therapeutic gain," he said.
>The complete article can be found at: http://www.hhmi.org/news/stamler.htm
>The reason that I think that this might be of interest to cryonet is
>it may have implications for the medication protocol that might be used to
>limit damage prior to or during suspension.  This is not my area of
>expertise - so someone knowledgeable may want to comment.
>Regards (and long life);

>Stephen Bogner, P.Eng.

The above post from Steven Bogner and Olaf Henry was the trigger I had
waited two years for.

The substance of the post is that the nitric oxide radical might be a
source of damage in ischemia, might be responsible for delayed neuronal
death, and "The reason that I think that this might be of interest to
cryonet is because it may have implications for the medication protocol
that might be used to limit damage prior to or during suspension.  This is
not my area of expertise - so someone knowledgeable may want to comment."

I accept Dr. Bogner's invitation. 

Since I left Alcor in circa 1992 I have been involved in research into the
mechanisms of cerebral and systemic ischemia-reperfusion injury and, in
particular, into the development of multimodal therapies aimed at
ameliorating this injury. Our endpoint has been _complete_ neurological
recovery to control levels following prolonged periods of warm
(normothermic) ischemia. Our goal is to reach the point where we can
routinely and uniformly (~90% of the time) resuscitate dogs from 30 minutes
of normotheric _total body_ cardiac arrest. This is much more difficult
than demonstrating recovery, acute or chronic, after isolated brain
ischemia where the multiple organ systems of the body continue to be
perfused without damage: damage which will greatly complicate and increase
the difficulty of achieving cerebral survival following such a long
interval of cardiac arrest.

We have currently reached the 17-minute mark. We have not done any further
work in this area for the past year because we have been involved with
development of a novel enabling technology that we believe will be critical
reaching the 30 minute mark. That work is now complete, and manuscripts are
in preparation.

When we began this work in 1992 all dogs subjected to 10 minutes of
ischemia were uniformly and catastrophically neuroinjured (persistent
vegatative state). Dog and man share a unique and surprisingly tight
overlap in both time-course and mechanisms of injury after cardiac arrest.
We learned early on that any initial recovery was followed by setbacks and
that the only truly valid model was evaluation of performance at 3 months
or more _post insult._  We strongly suspected apoptosis (programmed cell
death) and delayed necrotic cell death to be a major culprit, and were soon
able to prove that this was so. FYI, the particular caspases involved in
triggering aopoptic death are caspase 1 and, more importanly, caspase 3.

By 1993 I had a very good idea of what the primary mechanisms of injury
were in both the CNS and the body as a whole as a result of doing a
dipstick check for a urinary tract infection in a post-resuscitation dog
who had received the _very best_ in pharmacological, hemodynamic, and
hypothermic intervention, with the net result being a persistent vegetative
state. The test was positive, but the bacterial cultures were subsequently
and definitively negative, as was the evidence from the necropsy.
Subsequent evaluations showed the presence of high levels of nitrite in the
urine of  all ischemic dogs. Nitrite is normally present in urine only as a
result of the action of bacteria on nitrogen containing compounds in the
urine such as urea, so even increased nitrogen catabolism from the ischemic
insult would not account for the nitrite. Furthermore, control dogs had
higher nitrite levels than experimentals.

I will not bore you with the tortuous trail that I followed to understand
WHERE the nitrite was coming from. Suffice it to say that I was well aware
that the distribution of blood flow to tissues in health and disease was
largely mediated by nitric oxide. Further, I was intensely aware that
nitric oxide was produced in the brain by a special enzyme, bNOS, which is
distinct from those present in the circulatory system (i.e., inducible
nitric oxide synthase = iNOS and endogenous constitutive nitric oxide
synthase = ecNOS). In fact, just a few years before I left Alcor, Hugh
Hixon had been running around the Alcor faciliuty in Riverside waving a
copy of SCIENCE NEWS and expressing wonderment that the brain used nitric
oxide as a neurotransmitter (I've news for you Hugh, it uses carbon
monoxide too!).

In 1993 I had a number of papers from a symposium held in Shizuoka, Japan
on nitric oxide's role in neurotoxicity. These papers were in Japanese, but
short synopses were available in english. A year later CRC press published
the proeedings of that conference NITRIC OXIDE: Roles in Neuronal
Communication and Neurotoxicity. I paid the nearly $200 that slim volume
cost and have never regretted the expense. As it turns out, the really
nasty radical isn't nitric oxide, but rather peroxynitrite (.ONOO-).

I (and Jerry Leaf and I earlier) had already tried a number of approaches
to inhibiting ischemic injury including the use of two free radical
scavengers. All with dismal outcome. I was becoming increasingly convinced
that cerbral ischemia (and systemic) ischemia-reperfusion injury was
multifactorial and thus would require multimodal intervention. 

As I saw it, a major "error" in past thinking, just as in the case of
trying to block inappropriate immune inflammatory signal molecules in the
systemic immune inflammatory response (SIRS) (something all slowly dying
cryopatients experience and which ends in multisystem organ failure
(MSOF)), has been to single out one species of free radical as the culprit
in some injury, and go after it in isolation. Early on, in ischemia and
SIRS research, the focus was on the hydroxyl radical (.OH-), then it
shifted to the superoxide radical ion (.O2-), and more recently has focused
on the interaction of the nitric oxide molecule (.NO), which also happens
to be a free radical, with superoxide, which is another radical, which
together interact to create the very damaging peroxynitrite radical
(.ONOO-). New species of reactive radicals in the body seem to be
discovered regularly.

I might also add that each of these radical species can generate other
radicals, via multiple pathways. When a radical molecule takes an electron
another molecule which already has all of its electrons in pairs, it
creates a radical in the other molecule when it stops becoming one itself.
Thus, a long game of musical chairs begins, with each molecule stealing
from another, until the chain is finally ended by two radicals reacting
with each other (often one of these is a sacrificial antioxidant vitamin
molecule, like vitamin C, which can take two extra electrons, and wind up
with one less double bond). Meanwhile, this game of musical chairs has
potentially damaged vast numbers of biomolecules -- some of which are
criticalto cell survival. 

The modern organism, after a long evolution of living in oxygen (a double
radical molecule with two unpaired electrons, each in a separate outer
orbital), has as a consequence developed many, many different traps and
defenses against free
radical damage from having to metabolize oxygen. The take-home message here
that it is likely that most, if not all, of these radical species, are
significant sources of injury in SIRS and certainly in ischemia. Dealing
with one of them in isolation, such as the use of PEG-conjugated superoxide
dismutase for the superoxide radical, or mannitol for the hydroxyl radical,
is likely to be clinically futile. A good analogy would be locking just one
of your car doors to protect against against car-thieves.

Most of these radicals are alike, most of them do their damage by stealing
electrons from the double bonds of unsaturated fatty acids in cell
membranes, and making mutations and breaks in your DNA. But, alike doesn't
mean the _same._

The work of many other fine scientists was proceeding in this area during
this tme. In particular, Szabo Sabo and his colleagues began to unravel
just how damaging peroxynitrite was, and Szabo identified the mechanism by
which lipid peroxidation of the mitochondrial membrane resulted in the
formation of permanent holes or pores that allowed the leakage of
cytochromes into the cytoplasm where they triggered two very nasty
processes: poly-ADP-ribosylation synthase activation, and the activation of
caspases 1 and 3. The former resulted in rapid and sustained depletion of
ATP levels in a futile attempt to repair DNA damaged by all the free
radicals generated during ischemia-reperfusion, and the latter triggered
programmed cell death, or apoptosis as it properly called.

My focus was to develop a multi-modal approach to treating ischemic injury
and above all, to find a way to deliver a diverse array of radical
scavengers across the blood barrier in a time frame of _seconds_.  At the
top of my list was a peroxynitrite scavenger. Further down were iNOS and
bNOS inhibitors which did not do more harm than they did good. Unselective
NOS scavengers were disasters, and caused acute death of the animals.
Something sophisticated was needed.

In 1994 we did the first experiment using a "sophisticated approach." The
dog was walking around 24 hours after 14 minutes and 45 seconds of
normothermic ischemia and was christened "Cerberus." She was neurologically
normal that day, and she recognized the staff and wagged her tail
vigorously when Sandra Russell (her favorite person) approached.

People in the cryonis community were kept appraised of this. Certainly the
leaders of the cryonics organizations were informed. So too was a broad
cross section of the membership. After the Visser fiasco I was asked to
present our work on Cerebral Resuscitation at the Alcor Cryonics Conference
held in Phoenix, Az in April of 1998. One of our 16 minute dogs was brought
to the conference, and the general mechanics of the approach used to
achieve successful systemic and cerebral resuscitation were outlined in
considerable detail; including the critical importance of selective
inhibition of nitric oxide and the criticality of scavenging the
peroxynitrite radical.

This work, done by Steve Harris, Sandra Russell, Joan O'Farrell, Chris
Rasch, Carlotta Pengelley and myself, was apparently understood by the 150
or so people present.

The direct structural damage done by free radicals during _both_ ischemia
and reperfusion is profound. However, it pales in comparison to the damage
done by SIRS and MSOF which many cryonics patients will experience as part
of the dying process before their hearts ever stop beating.

The technology to block or mitigate this injury has existed since 1994 and
has been greatly improvd upon since.

Similarly, for those who attended the 21st Century Medicne Conference it
should be obvious that even more dramatic advances have been made in
mitigating cryoinjury. Few who did not come to the conference ordered the
tapes, and fewer still seem to have watched them. It is certainly the case
that almost no one cared enough about any of this progress to do anything
about it.

I opened CRYONICS magazine today and found an article by Linda Chamberlain
about the horrors of HMO healthcare and her own sad experience. Linda
pointed to a system that is essentially collectivist and concerned not with
the doctor-patient relationship, but rather with decision making for the
benefit of the "membership" and cost containment as being the root of her
own agonizing experience with what can only be termed as in my opinion, a
grossly negligent series of medical mis-steps that lead to a pneumothorax,
severe pain, and a very real risk of loss of life.

Linda was fortunate. Doubly fortunate. She lived _and_ she got the
opportunity to complain and warn others about the problem. She is unikely
to settle for substandard medical care in the future, and she is very
likely to be conscious of both the risks, and the advantages to upgrading
(when you can afford it) to a higher level of health care services. 
Certainly she will be more vigilant and assertive when putting her life on
the line.

Before Linda's bad experience she was enthusiastic about the quality of
medical care her HMO provided (it actually _is_ one of the better ones). I
vividly recall several conversations with her and Fred on just this matter;
in particular my loathing of the gutting and socialization of medicine and
the destruction of the doctor-patient relationship. 

But what does Linda's plight have to do with this post, or cryonics for
that matter? Quite a lot, really. Cryonics organizations, as it turns out,
are much like HMOs. They make decisions about the technology their members
get -- or don't get "for their own good." They make these decisions with a
cross-section or a majority of their "members" in mind. They make these
decisions with cost-containment and affordability in mind. They do not make
them on a one on one basis with members as physicians used to do,
explaining what is available, and what the cost-benefit trade offs are.
They determine what is available and you trust them to make the right
choices for _you._ You can see how well this is working out in healthcare.

In fairness to cryonics organizations, they have little incentive to behave
otherwise. They are virtually all non-profit socialist enterprises with
their members each expecting to be served steak and lobster when dinner
time comes, and not worrying much about the bill or who's picking up the

Even more to the point, the members of these organizations are in no
position to complain once dinner has been served -- or treatment given.
Cryopreservation is, after all, for the forseeable future anyway, a one-way
trip with no reports of happy outcomes or adverse reactions. There are no
cryopreserved patients struggling for breath, trying to remember who they
were, or dealing with a fragmented and disrupted sense of self. Or, for
that matter dealing with no self at all. 

There is no feedback. No normal corrective market mechanisms; no crippled
patient, no person in pain, no loss suffered and reported upon. 

Not yet. 

And, just like Linda, and millions of others like her, they won't worry
about the problem with HMOs or cryonics, until they become personal. The
problem is, they may not be as lucky as Linda was on either score, and in
any event, they certainly won't be telling any of us NOW about how happy or
dissatisfied they are with their cryonics care.

So we have a unique situation now. For 30 years I worked and dreamed of a
day when the cryonics community would have access to technology that would
vitrtually eliminate ultrastructural damage to the brain after
cryopreservation. I dreamed of being able to recover animals from 15
minutes of normothermic ischemia, let alone 17. And, if you think those two
extra minutes don't count for much, I'll quote the dean of cerebral
resuscitation himself, Dr. Peter Safar, as he recently summed up his career
to me: "When we strated this work 30 years ago we could, with great effort,
recover most dogs from 8 minutes of normothermic ischemia with lasting good
neurological outcome. We are now able to do this after 11 minutes about
half to three-quarters of the time. That works out to about 1 minute of
progress per decade of work." 

One minute per 10 years. We've added 6 minutes in 5 years. Four years, in
reality, since the last year has been spent on perfecting non-invasive
rapid induction of hypothermia using liquid ventilation: again with outcome
= long term _normal_ survival of the animals as a goal.

So, you can imagine my amusement when I read Bogner's and Henry's post
reproduced above. WOW! Nitric oxide might be important in ischemia. Maybe
we should _DO_ somethig about this. Well, gentlemen, the first cryonics
patient who had something done about it was a CryoCare member named James
Gallagher who had the advantage of peroxynitrite scavenging, iNOS
inhibition, bNOS inhibition and multimodal treatment of ischemia coupled
with rapid and effective restoration of good cerebral blood flows and
oxygenation. This happened in December of 1995. It could have happened to
any other cryopatient frozen with any reasonable warning of impending death
essentially any time after early 1994.  But it didn't.

I suppose that in the next 12 months somewhere between 3 and 12 people will
cryopreserved in the United States. If it is a bad year, that number might
be as high as 20 (I participated in 10 cases the last 12 months of my
tenure at Alcor).

The technology to vastly decrease both ischemic damage and cryoinjury now
exists and is implementable in a cost-effective fashion. It will NOT be
used on these people. In fact, arguably it will not be used on anybody for
a long while yet. My dog Cannibal may be the first to get it, and he
unarguably deserves it more than the vast majority of the rest of you. 

With a handful of exceptions, only people such as Saul Kent, Bill Faloon,
and the stalwarts that have worked, and supported the work, to make these
advances are the only other people remotely deserving of benefit from them.

I will be leaving an active role as a service provider in cryonics as of 25
June, 1999. It will have been after 31 years. When I first got involved
with cryonics I was 13 years old and I expected a lot of surprises. It is
fair to say I was certain only that cryonics represented a true marvel: the
technology of tomorrow available today.

I leave considerably wiser.

 And the irony is not lost on me that cryonics as it exist now is not
tomorrow;s technology today, but yesterday's technlogy today _and_ tomorrow
(and probably the day after, too).

If we here at the lab are fortunate enough to re-start our resuscitation
work in a month or so as planned, cryonics will soon be the day _before_
yesterday's technology -- tomorrow.

I have said my piece. Now, it is time for me to follow Voltaire's advice
spoken so wisely by Candide: "It is time to return to work in the garden."

To the rest of you cryonicists, men and women of not inconsiderable
intelligence or resources, I say with honesty and with no malice, return to
your Panglossian debates "in this, the best of all possible worlds," and I
promise, for my part, not to interrupt you so rudely again.

Mike Darwin

Speaking solely on his own  behalf and in consultation with no one
regarding this post.

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