From: merkle@parc.xerox.com (Ralph Merkle)
Subject: The Technical Feasibility of Cryonics; part #4
Organization: Xerox PARC
Date: 22 Nov 92 21:17:02 GMT

The Technical Feasibility of Cryonics

PART 4 of 5.

by

Ralph C. Merkle
Xerox PARC
3333 Coyote Hill Road
Palo Alto, CA 94304
merkle@xerox.com

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.


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