NetNews Usenet Archive 1992 #27/NN_1992_27.iso/spool/sci/cryonics/654

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From: [e-mail] (Ralph Merkle)
Subject: The Technical Feasibility of Cryonics; part #4
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Date: 22 Nov 92 21:17:02 GMT
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The Technical Feasibility of Cryonics

PART 4 of 5.

by

Ralph C. Merkle
Xerox PARC
3333 Coyote Hill Road
Palo Alto, CA 94304
[e-mail]

A shorter version of this article appeared in:
Medical Hypotheses (1992)  39, pages 6-16.


----------------------------------------------------------
     Determining the Healthy State

In the second phase of the analysis, determination of the healthy state,
we determine what the repaired (healthy) tissue should look like at the
molecular level.  That is, the initial structural data base produced by
the analysis phase describes unhealthy (frozen) tissue.  In
determination of the healthy state, we must generate a revised
structural data base that describes the corresponding healthy
(functional) tissue.   The generation of this revised data base requires
a computer program that has an intimate understanding of what healthy
tissue should look like, and the correspondence between unhealthy
(frozen) tissue and the corresponding healthy tissue.  As an example,
this program would have to understand that healthy tissue does not have
fractures in it, and that if any fractures are present in the initial
data base (describing the frozen tissue) then the revised data base
(describing the resulting healthy tissue) should be altered to remove
them.  Similarly, if the initial data base describes tissue with swollen
or non-functional mitochondria, then the revised data base should be
altered so that it describes fully functional mitochondria.  If the
initial data base describes tissue which is infected (viral or bacterial
infestations) then the revised data base should be altered to remove the
viral or bacterial components.

While the revised data base describes the healthy state of the tissue
that we desire to achieve, it does not specify the method(s) to be used
in restoring the healthy structure.  There is in general no necessary
implication that restoration will or will not be done at some specific
temperature, or will or will not be done in any particular fashion.  Any
one of a wide variety of methods could be employed to actually restore
the specified structure.  Further, the actual restored structure might
differ in minor details from the structure described by the revised data
base.

The complexity of the program that determines the healthy state will
vary with the quality of the suspension and the level of damage prior to
suspension.  Clearly, if cryonic suspension "almost works", then the
initial data base and the revised data base will not greatly differ.
Cryonic suspension under favorable circumstances preserves the tissue
with remarkable fidelity down to the molecular level.  If, however,
there was significant pre-suspension injury then deducing the correct
(healthy) structural description is more complex.  However, it should be
feasible to deduce the correct structural description even in the face
of significant damage.  Only if the structure is obliterated beyond
recognition will it be infeasible to deduce the undamaged state of the
structure.

ALTERNATIVES TO REPAIR

A brief philosophical aside is in order.  Once we have generated an
acceptable revised structural data base, we can in fact pursue either of
two distinctly different possibilities.  The obvious path is to continue
with the repair process, eventually producing healthy tissue.  An
alternative path is to use the description in the revised structural
data base to guide the construction of a different but "equivalent"
structure (e.g., an "artificial brain").  This possibility has been much
discussed[11, 50], and has recently been called "uploading" (or
"downloading")[26].  Whether or not such a process preserves what is
essentially human is often hotly debated, but it has advantages wholly
unrelated to personal survival.  As an example, the knowledge and skills
of an Einstein or Turing need not be lost:  they could be preserved in a
computational model.  On a more commercial level, the creative skills of
a Spielberg (whose movies have produced a combined revenue in the
billions) could also be preserved.  Whether or not the computational
model was viewed as having the same essential character as the
biological human after which it was patterned, it would indisputably
preserve that person's mental abilities and talents.

It seems likely that many people today will want complete physical
restoration (despite the philosophical possibilities considered above)
and will continue through the repair planning and repair phases.

RESTORATION

In the third phase of repair we start with an atomically precise
description (the revised data base) of the structure that we wish to
restore, and a filing cabinet holding the molecules that will be needed
during restoration.  Optionally, the molecules in the filing cabinet can
be from the original structure.  This deals with the concerns of those
who want restoration with the original atoms.  Our objective is to
restore the original structure with a precision sufficient to support
the original functional capabilities.  Clearly, this would be achieved
if we were to restore the structure with atomic precision.  Before
discussing this most technically exacting approach, we will briefly
mention the other major approaches that might be employed.

We know it is possible to build a human brain, for this has been done by
traditional methods for many thousands of years.  If we were to adopt a
restoration method that was as close as possible to the traditional
technique for building a brain, we might use a "guided growth" strategy.
That is, in simple organisms the growth of every single cell and of
every single synapse is determined genetically.  "All the cell
divisions, deaths, and migrations that generate the embryonic, then the
larval, and finally the adult forms of the roundworm Caenorhabditis
Elegans have now been traced."[103].  "The embryonic lineage is highly
invariant, as are the fates of the cells to which it gives rise"[102].
The appendix says:  "Parts List: Caenorhabditis elegans (Bristol) Newly
Hatched Larva.  This index was prepared by condensing a list of all
cells in the adult animal, then adding comments and references.  A
complete listing is available on request..."  The adult organism has 959
cells in its body, 302 of which are nerve cells[104].

Restoring a specific biological structure using this approach would
require that we determine the total number and precise growth patterns
of all the cells involved.  The human brain has roughly 10^12 nerve
cells, plus perhaps ten times as many glial cells and other support
cells.  While simply encoding this complex a structure into the genome
of a single embryo might prove to be overly complex, it would certainly
be feasible to control critical cellular activities by the use of on
board nanocomputers.  That is, each cell would be controlled by an on-
board computer, and that computer would in turn have been programmed
with a detailed description of the growth pattern and connections of
that particular cell.  While the cell would function normally in most
respects, critical cellular activities, such as replication, motility,
and synapse growth, would be under the direct control of the on-board
computer.  Thus, as in C. Elegans but on a larger scale, the growth of
the entire system would be "highly invariant."  Once the correct final
configuration had been achieved, the on-board nanocomputers would
terminate their activities and be flushed from the system as waste.

This approach might be criticized on the grounds that the resulting
person was a "mere duplicate," and so "self" had not been preserved.
Certainly, precise atomic control of the structure would appear to be
difficult to achieve using guided growth, for biological systems do not
normally control the precise placement of individual molecules.  While
the same atoms could be used as in the original, it would seem difficult
to guarantee that they would be in the same places.

Concerns of this sort lead to restoration methods that provide higher
precision.  In these methods, the desired structure is built directly
from molecular components by placing the molecular components in the
desired locations.  A problem with this approach is the stability of the
structure during restoration.  Molecules might drift away from their
assigned locations, destroying the structure.

An approach that we might call "minimal stabilization" would involve
synthesis in liquid water, with mechanical stabilization of the various
lipid membranes in the system.  A three-dimensional grid or scaffolding
would provide a framework that would hold membrane anchors in precise
locations.  The membranes themselves would thus be prevented from
drifting too far from their assigned locations.  To prevent chemical
deterioration during restoration, it would be necessary to remove all
reactive compounds (e.g., oxygen).

In this scenario, once the initial membrane "framework" was in place and
held in place by the scaffolding, further molecules would be brought
into the structure and put in the correct locations.  In many instances,
such molecules could be allowed to diffuse freely within the cellular
compartment into which they had been introduced.   In some instances,
further control would be necessary.  For example, a membrane-spanning
channel protein might have to be confined to a specific region of a
nerve cell membrane, and prevented from diffusing freely to other
regions of the membrane.  One method of achieving this limited kind of
control over further diffusion would be to enclose a region of the
membrane by a diffusion barrier (much like the the spread of oil on
water can be prevented by placing a floating barrier on the water).

While it is likely that some further cases would arise where it was
necessary to prevent or control diffusion, the emphasis in this method
is in providing the minimal control over molecular position that is
needed to restore the structure.

While this approach does not achieve atomically precise restoration of
the original structure, the kinds of changes that are introduced
(diffusion of a molecule within a cellular compartment, diffusion of a
membrane protein within the membrane) would be very similar to the kinds
of diffusion that would take place in a normal biological system.  Thus,
the restored result would have the same molecules with the same atoms,
and the molecules would be in similar (though not exactly the same)
locations they had been in prior to restoration.

To achieve even more precise control over the restored structure, we
might adopt a "full stabilization" strategy.  In this strategy, each
major molecule would be anchored in place, either to the scaffolding or
an adjacent molecule.  This would require the design of a stabilizing
molecule for each specific type of molecule found in the body.   The
stabilizing molecule would have a specific end attached to the specific
molecule, and a general end attached either to the scaffolding or to
another stabilizing molecule.  Once restoration was complete, the
stabilizing molecules would release the molecules that were being
stabilized and normal function would resume.  This release might be
triggered by the simple diffusion of an enzyme that attacked and broke
up the stabilizing molecules.  This kind of approach was considered by
Drexler[1].

     Low Temperature Restoration

Finally, we might achieve stability of the intermediate structure by
using low temperatures.  If the structure were restored at a
sufficiently low temperature, a molecule put in a certain place would
simply not move.  We might call this method "low temperature
restoration."

In this scenario, each new molecule would simply be stacked (at low
temperature) in the right location.  This can be roughly likened to
stacking bricks to build a house.  A hemoglobin molecule could simply be
thrown into the middle of the half-restored red blood cell.  Other
molecules whose precise position was not critical could likewise be
positioned rather inexactly.  Lipids in the lipid bi-layer forming the
cellular membrane would have to be placed more precisely (probably with
an accuracy of several angstroms).  An individual lipid molecule, having
once been positioned more or less correctly on a lipid bi-layer under
construction, would be held in place (at sufficiently low temperatures)
by van der Waals forces.  Membrane bound proteins could also be
"stacked" in their proper locations.  Because biological systems make
extensive use of self-assembly, it would not be necessary to achieve
perfect accuracy in the restoration process.  If a biological
macromolecule is positioned with reasonable accuracy, it would
automatically assume the correct position upon warming.

Large polymers, used either for structural or other purposes, pose
special problems.  The monomeric units are covalently bonded to each
other, and so simple "stacking" is inadequate.  If such polymers cannot
be added to the structure as entirely pre-formed units, then they could
be incrementally restored during assembly from their individual monomers
using the techniques discussed earlier involving positional synthesis
using highly reactive intermediates.  Addition of monomeric units to the
polymer could then be done at the most convenient point during the
restoration operation.

The chemical operations required to make a polymer from its monomeric
units at reduced temperatures are unlikely to use the same reaction
pathways that are used by living systems.  In particular, the activation
energies of most reactions that take place at 310 K (98.6 degrees
Fahrenheit) can not be met at 77 K: most conventional compounds don't
react at that temperature.  However, as discussed earlier, assembler
based synthesis techniques using highly reactive intermediates in near-
perfect vacuum with mechanical force providing activation energy will
continue to work quite well, if we assume that thermal activation energy
is entirely absent (e.g., that the system is close to 0 kelvins).

An obvious problem with this approach is the need to re-warm the
structure without incurring further damage.   Much "freezing" injury
takes place during rewarming, and this would have to be prevented.  One
solution is discussed in the next two paragraphs.

Generally, the revised structural data base can be further altered to
make restoration easier.  While certain alterations to the structural
data base must be banned (anything that might damage memory, for
example) many alterations would be quite safe.  One set of safe
alterations would be those that correspond to real-world changes that
are non-damaging.  For example, moving sub-cellular organelles within a
cell would be safe - such motion occurs spontaneously in living tissue.
Likewise, small changes in the precise physical location of cell
structures that did not alter cellular topology would also be safe.
Indeed, some operations that might at first appear dubious are almost
certainly safe.  For example, any alteration that produces damage that
can be repaired by the tissue itself once it is restored to a functional
state is in fact safe - though we might well seek to avoid such
alterations (and they do not appear necessary).   While the exact range
of alterations that can be safely applied to the structural data base is
unclear, it is evident that the range is fairly wide.

An obvious modification which would allow us to re-warm the structure
safely would be to add cryoprotectants.  Because we are restoring the
frozen structure with atomic precision, we could use different
concentrations and different types of cryoprotectants in different
regions, thus matching the cryoprotectant requirements with exquisite
accuracy to the tissue type.  This is not feasible with present
technology because cryoprotectants are introduced using simple diffusive
technniques.

Extremely precise control over the heating rate would also be feasible,
as well as very rapid heating.  Rapid heating would allow less time for
damage to take place.  Rapid heating, however, might introduce problems
of stress and resulting fractures.  Two approaches for the elimination
of this problem are (1) modify the structure so that the coefficient of
thermal expansion is very small and (2) increase the strength of the
structure.

One simple method of insuring that the volume occupied before and after
warming was the same (i.e., of making a material with a very small
thermal expansion coefficient) would be to disperse many small regions
with the opposite thermal expansion tendency throughout the material.
For example, if a volume tended to expand upon warming the initial
structure could include "nanovacuoles," or regions of about a nanometer
in diameter which were empty.   Such regions would be stable at low
temperatures but would collapse upon warming.  By finely dispersing such
nanovacuoles it would be possible to eliminate any tendency of even
small regions to expand on heating.  Most materials expand upon warming,
a tendency which can be countered by the use of nanovacuoles.

Of course, ice has a smaller volume after it melts.  The introduction of
nanovacuoles would only exacerbate its tendency to shrink upon melting.
In this case we could use vitrified H20 rather than the usual
crystalline variety.  H20 in the vitreous state is disordered (as in the
liquid state) even at low temperatures, and has a lower volume than
crystalline ice.  This eliminates and even reverses its tendency to
contract on warming.  Vitrified water at low temperature is denser than
liquid water at room temperature.

Increasing the strength of the material can be done in any of a variety
of ways.  A simple method would be to introduce long polymers in the
frozen structure.  Proteins are one class of strong polymer that could
be incorporated into the structure with minimal tissue compatibility
concerns.  Proteins of substantially greater length than naturally
existing proteins would be particularly effective at increasing
strength.  Any potential fracture plain would be criss-crossed by the
newly added structural protein, and so fractures would be prevented.  By
also including an enzyme to degrade this artificially introduced
structural protein, it would be automatically and spontaneously digested
immediately after warming.  Very large increases in strength could be
achieved by this method.

By combining (1) rapid, highly controlled heating with (2) atomically
precise introduction of cryoprotectants; (3) the addition of small
nanovacuoles and the use of vitrified H20 to reduce or eliminate thermal
expansion and contraction; and (4) the addition of structural proteins
to protect against any remaining thermally induced stresses; the damage
that might otherwise occur during rewarming should be completely
avoidable.



CONCLUSION

Cryonic suspension can transport a terminally ill patient to future
medical technology.  The damage done by current freezing methods is
likely to be reversible at some point in the future.  In general, for
cryonics to fail, one of the following "failure criteria" must be met:

1.)  Pre-suspension and suspension injury would have to be sufficient to
cause information theoretic death.  In the case of the human brain, the
damage would have to obliterate the structures encoding human memory and
personality beyond recognition.

2.)  Repair technologies that are clearly feasible in principle based on
our current understanding of physics and chemistry would have to remain
undeveloped in practice, even after several centuries.

An examination of potential future technologies[85] supports the
argument that unprecedented capabilities are likely to be developed.
Restoration of the brain down to the molecular level should eventually
prove technically feasible.  Off-board repair utilizing divide-and-
conquer is a particularly simple and powerful method which illustrates
some of the principles that can be used by future technologies to
restore tissue.  Calculations support the idea that this method, if
implemented, would be able to repair the human brain within about three
years.  For several reasons, better methods are likely to be developed
and used in practice.

Off-board repair consists of three major steps:  (1) Determine the
coordinates and orientation of each major molecule.  (2) Determine a set
of appropriate coordinates in the repaired structure for each major
molecule.  (3)  Move them from the former location to the latter.  The
various technical problems involved are likely to be met by future
advances in technology.  Because storage times in liquid nitrogen
literally extend for several centuries, the development time of these
technologies is not critical.

A broad range of technical approaches to this problem are feasible.  The
particular form of off-board repair that uses divide-and-conquer
requires only that (1) tissue can be divided by some means (such as
fracturing) which does not itself cause significant loss of structural
information;  (2) the pieces into which the tissue is divided can be
moved to appropriate destinations (for further division or for direct
analysis); (3) a sufficiently small piece of tissue can be analyzed; (4)
a program capable of determining the healthy state of tissue given the
unhealthy state is feasible; (5) that sufficient computational resources
for execution of this program in a reasonable time frame are available;
and (6) that restoration of the original structure given a detailed
description of that structure is feasible.

It is impossible to conclude based on present evidence that either
failure criterion is likely to be met.

Further study of cryonics by the technical community is needed.  At
present, there is a remarkable paucity of technical papers on the
subject[ft. 22].  As should be evident from this paper multidisciplinary
analyis is essential in evaluating its feasibility, for specialists in
any single discipline have a background which is too narrow to encompass
the whole.  Given the life-saving nature of cryonics, it would be tragic
if it were to prove feasible but was little used.


APPENDIX

Approximate values of interesting numbers.  Numbers marked by * are
extrapolations based on projected technical capabilities (nanotechnology
and molecular computing).



Volume of the brain:                     1350 cubic centimeters
Weight of the brain:                     1400 grams
Weight of proteins in the brain:         100 grams
Weight of a ribosome:                    3 x 10^6 amu
*Weight of a repair machine:             10^9 to 10^10 amu

*Length of a repair machine arm:         100 nanometers
Weight of water in brain:                1100 grams
Weight of protein in brain:              100 grams
Weight of lipids in brain:               175 grams
Weight of "other solids":                35 grams

Weight of "typical" protein:             50,000 amu
Weight of "typical" lipid:               500 amu
Weight of water molecule:                18 amu
Weight of carbon atom:                   12 amu
Density of carbon (diamond):             3.51 grams/cubic centimeter

Number of proteins in brain:             1.2 x 10^21
Number of lipid molecules in brain:      2 x 10^23
Number of water molecules in brain:      4 x 10^25
Time to synthesize a protein:            10 seconds
*Time to repair one protein molecule:    100 seconds

*Time to repair one lipid molecule:      1 second
*Time to repair all brain macromolecules:3.2 x 10^23
                                           repair-machine seconds
*Number of repair machines to
     repair all brain molecules in
     three years:                        3.2 x 10^15 repair machines
*Weight of that many repair devices:     53 to 530 grams
Number of bits needed to store the
     molecular structure of the brain:   10^25 bits

*Energy dissipated by a single "rod
     logic" (gate) operation
     (including a few percent
     of irreversible operations):        10^-22 joules
*Speed of a single "rod logic"
     (gate) operation:                   100 x 10^-12 seconds
Estimated cost of 10^15 joules of energy
     generated on earth in the future:   10,000 dollars
*Number of gate operations 10^15
     joules can support:                 10^37 gate operations
*Size of a single "lock" (gate)
     plus overhead (power, etc):         100 cubic nanometers

*Volume of gates that can
     deliver 10^37 operations in
     three years (a larger volume will
     in fact be required to accomodate
     cooling requirements):              1 cubic centimeter
Power of 10^15 joules dissipated
     over a three year period:           10 megawatts (10^5 light bulbs
                                             for three years)
Chemical energy stored in the
     structure of the brain:             8 x 10^6 joules (2,000 kilocalories)

Boltzman's constant k:                   1.38 x 10^-23 joules/Kelvin
Approximate thermal energy of
     one atom at room temperature
     (kT at 300 degrees K):              4.14 x 10^-21 joules
One watt:                                one joule per second
One kilowatt hour:                       3.6 x 10^6 joules
Avogadro's number (the number of
     atoms in one mole):                 6.0221367 x 10^23

One mole of a substance:                 that quantity of the
                                             substance that weighs
                                             (in grams) the same as
                                             its molecular weight
amu (atomic mass units):                 By definition, one atom
                                             of carbon 12 weighs
                                             12 amu
Joules per (dietary) Calorie:           4,186



ACKNOWLEDGEMENTS

It is the authors pleasant duty to acknowledge the many people who have
commented on or encouraged the work on this paper as it evolved.  The
reviewers were not selected because of their opinions about cryonics:
some support it, some don't, and some reserve final judgement.  While
the quality of the result could not have been achieved without their
help, the author must accept responsibility for any errors in the final
version.  The author would like to thank:  Dave Biegelsen, Arthur C.
Clarke, Mike Darwin, Thomas Donaldson, Eric Drexler, Greg Fahy, Steve
Harris, Leonard Hayflick, Hugh Hixon, Peter Mazur, Mark Miller, David
Pegg, Chris Peterson, Ed Regis, Paul Segall, Len Shar, Irwin Sobel, Jim
Southard, Jim Stevens and Leonard Zubkoff.