The Arrest of Biological Time
as a Bridge to Engineered Negligible Senescence
By Jerry Lemler, M.D., Steven B. Harris, M.D, Charles Platt, and Todd M. Huffman
This talk by Alcor's Medical Director, Dr. Jerry Lemler, was delivered at the
of The International Association of Biomedical Gerontology at Queen's College,
Cambridge, England, September 19-23, 2003. The corresponding paper was published
in the Annals
of the New York Academy of Sciences (2004 vol. 1019), pg. 559-563. See the complete text of this paper.
Biological systems can remain unchanged for several hundred years at cryogenic
temperatures. In several hundred years, current rapid scientific and technical
progress should lead to the ability to reverse any biological damage whose reversal
is not forbidden by physical law. We therefore explore whether contemporary
people facing terminal conditions might be preserved well enough today for their
eventual recovery to be compatible with physical law. The ultrastructure of
the brain can now be excellently preserved by vitrification, and solutions needed
for vitrification can now be distributed through organs with retention of organ
viability after transplantation. Current law requires a few minutes of cardiac
arrest before cryopreservation of terminal patients, but dogs and cats have
recovered excellent brain function after 16-60 min of complete cerebral ischemia.
The arrest of biological time as a bridge to engineered negligible senescence,
therefore, appears consistent with current scientific and medical knowledge.
The Arrest of Biological Time
as a Bridge to
Engineered Negligible Senescence
Jerry B. Lemler, M.D., Medical Director
Alcor Life Extension Foundation
Scottsdale, AZ, USA
|First of all I would like to thank Aubrey for inviting me to give this talk. It is my pleasure to discuss with this audience the concept of putting biological time on hold so as to create a bridge to both engineered negligible senescence and other valuable medical technologies of the future.
Two Ways to Modify Biological Time
The egg cell serves as a “time machine” to take adult cells back
in biological time to potentially form autologous totipotent stem
|Very low temperatures serve as a “time machine” to take adult
cells forward in time in a changeless state until it is time to
|The opponent of the gerontologist is biological time. As you all heard from
Michael West earlier in this meeting, one way to conquer biological time has
been proposed in the form of nuclear transfer, in which a senescent cell or
its nucleus can be effectively taken back in biological time by being transferred
to the “time machine” of an egg cell. Equally familiar to this audience is
the phenomenon of the time machine provided by cryobiology, in which very
low temperatures allow living cells to be moved forward in objective time
while standing still in biological time until they are needed.
An Audacious Proposal:
The Concept of
“Medical Time Travel”
Many diseases and conditions that are incurable today
(including senescence!) will probably be curable at some time in
If the patients of today were able to benefit from the medical technologies
of the future, many terminal patients could probably be rescued.
Could cryobiological time arrest allow today’s
patients to wait for future medicine?
|You all heard yesterday from Aubrey de Grey about his so-called crazy proposal
for the elimination of cancer in humans. In the same vein, I now offer you
another audacious proposal. The concept of what I’d like to call medical
time travel is simple. Most of you would agree that many diseases and
symptoms that are not presently curable probably will be curable sometime
in the future, and that if patients of today could somehow benefit from the
medical technology of the future, many people who are now considered terminal
could be rescued. The question we will now consider is, could the time machine
of cryobiology conceivably provide a way for today’s patients to wait for
A Basis for Medical “Time Travel”
||For all practical purposes, at approx. -196°C
biological changes do not occur over periods of centuries
||Medical technology will continue to improve. After several hundred
years, medicine will be able to reverse any injury whose reversal
is not forbidden by fundamental physical law.
||If patients can be cooled to approx.
-196°C today without producing injury
that is irreversible in principle, it
should be possible to recover today’s patients with the help of tomorrow’s
|We can start to think about this idea by putting together one fact and one
assumption. The fact is that for all practical purposes, at -196 degrees centigrade,
(the temperature of liquid nitrogen), biological changes do not occur, even
over periods lasting centuries to millennia. The assumption is that medical
technology will continue to improve for as long as the patient remains at
that temperature. It is possible to project that after several hundred years
medicine should be able to reverse any injury whose reversal is not forbidden
by the laws of physics and chemistry. Therefore, if patients can be stored
near liquid nitrogen temperature now without producing injury that is irreversible
in principle, then it should be possible eventually to recover today’s patients
with the benefit of tomorrow’s technology.
“Brief Proposal On Immortality:
An Interim Solution”
by George M. Martin
Perspectives in Biology
and Medicine 14(2): 339-340, 1971
|“. . . a . . . solution to the ‘terrible problem of death awareness’
. . . which appeals to me is one which preserves the central nervous
system. The spectacular success of cryobiological procedures . . . suggests
. . . satisfactory . . . preservation may yet be achieved . . . in
situ . . . .”
|You may find it interesting that Dr. George Martin thought the same way in
1971 when he said a solution to the whole problem of death awareness, which
appealed to him, is one that preserves the central nervous system, and that
the spectacular successes of cryobiological procedures suggest that satisfactory
preservation may be achievable in situ.
Is Today’s Injury Potentially Reversible?
1: today’s fatal diseases
e.g., heart disease, cancer, infectious diseases, the effects
Injury category 2:
brief anoxia after “clinical death”
(necessary under current law)
Injury category 3:
|Of course, this will only work if the injury induced today is potentially
reversible. We can identify three fundamental categories of injury to consider,
and these are: today’s fatal diseases, the anoxia associated with brief clinical
death, and cryopreservation injury. Clearly, the reversal of today’s fatal
diseases will require extensive research and time, but should be plausible
to this audience, as most of you are willing to seriously consider the prevention
and even the reversal of senescence. Consequently we will move on to the more
pressing issues of clinical death and cryopreservation injury.
Understanding “Clinical Death”
- A legal, not a biological, definition of death
- Cardiopulmonary arrest
- Not “brain death”
|Under current law it is necessary to have a physician declare legal death
before any attempt at cryopreservation can be made. Legal or clinical death
can be declared after there has been a short period of cardiopulmonary arrest,
after which resuscitation methods can be and routinely are applied. It is
important to distinguish this situation from that of brain death, which is
in no way required by current law as it pertains to our proposal.
Surviving Clinical Death
- Following cardiac arrest, injury will accumulate until a
rescue team is able to restore circulation and oxygenation.
- What is the safe window of time within which a team can act
before brain injury becomes irreversible by present technology?
|The risk for our proposal is that the brain will be anoxic during the time
required for the declaration of death itself, plus any time required for any
rescue team to restore circulation and oxygenation to the brain or to perform
other stabilizing procedures such as cooling. We therefore need to have an
idea of how much time the brain can be subjected to ischemia and still be
recovered without permanent injury. In other words, is there a window of opportunity
in which rescue teams can act?
Reversibility of Clinical Death:
Survival of Adult Dogs with Normal Mentation
Following 14-16 Min of Normothermic
Whole-Body Circulatory Arrest
*Tympanic temperature just before fibrillation; degrees Celsius
**Time with mean arterial pressure below 30 mmHg
|Contrary to the clinical impression that the limit for reversible brain anoxia
is only 5 minutes, we know the actual limit in dogs is at least 16 minutes,
because the dogs in this table were subjected to up to 16 minutes of normothermic
cardiac arrest with no pretreatment and they recovered without any brain damage
whatsoever. So we know the old 5 minute limit for reversibility of brain death
is in fact not a true biological limit.
Reversibility of Clinical Death: 2
|We also know that 16 minutes is not the limit because of Hossman’s cat. In
1987 his group reported that they had allowed a cat to survive a procedure
that completely stopped cerebral blood flow at normal body temperature for
one hour. After the procedure the cat recovered and survived indefinitely,
was able to walk, clean itself, recognize lab staff, and purr. This experiment
was the culmination of years of research by Hossmann and colleagues indicating
that brain injury is reversible in cats and monkeys after at least one hour
of complete normothermic cerebral ischemia.
Reversibility of Clinical Death: 3
Rapid Interruption of Warm Ischemic Injury
|So the true biological limit is at least 60 minutes, more than enough time
for a waiting rescue team to respond. In principle, a patient can be put into
an ice bath and cooled externally immediately after legal death is pronounced.
Cooling can be assisted by external cardiac compression using one of these
Lucas chest compression devices, along with oxygenation given by endotrachial
tube, and so the first stages of reversing brain anoxia can be instituted
quite rapidly, well within the period of reversibility of brain damage. Even
more advanced techniques of rapid cooling are feasible and practiced, further
reducing anoxic injury.
|This is a portable perfusion and cooling unit used to induce rapid whole
body hypothermia and initiate perfusion and reoxygenation. Note the perfusate
reservoirs and all necessary equipment to perform patient stabilization under
|And, as you can see in this diagram, the cooling rate you can achieve with
these devices is substantial, which further guarantees protection against
anoxic injury. The blue line represents the cooling rate achievable by perfusion.
Source: Cryobiology 21: 407-426, 1984.
Surviving Cryopreservation Injury
|Freezing (ice formation,
left) tears tissues
Vitrification (glass formation,
right) does not
|This leaves one remaining potential source of injury, and that’s cryopreservation
injury. In the old days cryopreservation used to be done by freezing. Freezing
is the formation of ice crystals. Ice crystals appear white when they form
in tissues, as you can see in the frozen kidney on the left. Unfortunately,
ice crystals also cause major damage to organized tissues, and that's why
we haven’t been using this process since the year 2000 at Alcor. Instead we
have been using a process called vitrification, which is the formation of
a glass. Glass formation does not permit ice crystals to develop, and therefore
there is no ice damage associated with glass formation. On the right you can
see that it is possible to vitrify a whole organ, which in this case is a
rabbit kidney. This kidney looks the same as a fresh kidney even though it
was photographed at 140 degrees below zero.
Source: Biodynamica 10: 193-210, 1968
|This slide explains the concept in more detail. As you gradually increase
the concentration of a cryoprotective agent, thereby replacing water, ice
formation diminishes. Here we see ice crystals inside a red blood cell getting
smaller and smaller and eventually disappearing altogether. At the highest
concentration even extracellular ice disappears despite cooling to cryogenic
temperatures. This is what we mean by vitrification.
|Recent experiments have shown that this process can actually be applied to
an entire brain. This is a scanning electron microscope image of some cerebral
cortex removed from a rabbit brain that was vitrified, rewarmed, and fixed
by vascular perfusion. The cryoprotectant was then gradually removed. The
surface of the brain is at the top, with white matter seen as the rough area
at the bottom. You can see a blood vessel near the top that is intact. Other
than a few mechanical artifacts, the substance of the cerebral cortex and
the underlying white matter is remarkably nice and smooth. There were no ice
|You can verify this by zooming in. You can see that the apparent holes in
the tissue are capillaries. Ice crystals would be massive on this scale, and
we don’t see any of them. Therefore, this brain actually did vitrify.
|This is the same cerebral cortex but seen by transmission electron microscopy.
The cortical pyramidal cells are osmotically shrunken and distorted but otherwise
appear to be intact. You can see shrunken axoplasm inside myelinated nerve
fibers. You also see normal-appearing capillaries. There are no ice crystals
anywhere to be seen, and as far as we can tell, the ultrastructure is fundamentally
preserved. The diagonal gap is an artifact.
|We also looked elsewhere in the brain. This happens to be the hippocampus.
|If you look at the hippocampus either by scanning or transmission electron
microscopy, again you see the same thing. No ice anywhere. The tissue is certainly
dehydrated, but you do not see structural disintegration, or clearly irreversible
damage to the ultrastructure.
|This is an area in the middle of the hippocampus, again showing all of the
neuropil compressed and dehydrated, but intact.
|This is the dentate gyrus, where the same picture is seen. This goes on for
field after field, slide after slide. I don’t want to bore you with it, but
no matter where we look we couldn’t see any evidence of ice formation, but
we do see preserved capillaries, shrunken cells, and intact neuropil.
Is Cryoprotectant Toxicity
Whole rabbit kidneys support life after
transplantation following perfusion with vitrification solutions.
Rat hippocampal slices survive vitrification
|So it looks like we can avoid the mechanical effects of ice in vitrifying
the brain, but what about the toxicity of the agents that are needed to replace
water? Do cryoprotectants have a toxic effect that’s irreversible in principle?
We think that’s unlikely, for a couple of reasons. For one thing, whole rabbit
kidneys were recently reported to support life after transplantation despite
perfusion with an ultrastable vitrification solution, M22, and were able to
bring serum creatinine levels down to normal. So if the damage caused by these
cryoprotectants is reversible spontaneously today it doesn’t seem likely that
it will be irreversible with the benefit of better technology in the future.
The other reason has to do with the brain itself. In particular, studies currently
being prepared for publication have shown that rat hippocampal slices can
actually survive vitrification and re-warming.
The major hazards of attempted
medical time travel
- Contemporary diseases
- Cerebral ischemia
- Mechanical tissue disruption by ice, &
- Toxic damage from vitrification solutions
all seem unlikely to require remedies
are impossible according to physical law.
|On the basis of all of this evidence, it seems to us that the major hazards
of attempted medical time travel, including diseases, ischemia, tissue disruption
by ice, and stress from vitrifying solutions, all seem unlikely to require
remedies that are incompatible with physical law.
… and therefore it is justified to regard attempted medical time
travel as a conservative approach to the treatment of otherwise
terminally ill patients.
|And therefore we believe it is justified to regard attempted medical time
travel as a conservative approach to otherwise terminally ill patients.
Reaching the Limits of Physical Law:
|If anyone would like to know more about how reaching the limits of physical
law in medicine might be achieved, I would be happy to refer you to several
scholarly works on the subject, such as these particularly outstanding books.
|In the meantime, thank you very much for your attention.