Molecular Repair of the Brain by Ralph C. Merkle, Ph.D.

This article was published in two parts in Cryonics magazine, January and April 1994. A more highly annotated version can be found on Ralph Merkle's Cryonics Pages.

See also cryobiologist Dr. Gregory Fahy's critique of this paper and Dr. Merkle's response. For an alternative repair scenario contributed by an anonymous biologist that circumvents Dr. Fahy's concerns, see "Realistic Scenario for Nanotechnological Repair of the Frozen Human Brain".

A short version of this paper entitled "The Technical Feasibility of Cryonics," appeared in Medical Hypotheses Vol. 39, 1992; 6-16.

CONTENTS

Cryonic suspension is a method of stabilizing the condition of someone who is terminally ill so that they can be transported to the medical care facilities that will be available in the late 21st or 22nd century. There is little dispute that the condition of a person stored at the temperature of liquid nitrogen is stable, but the process of freezing inflicts a level of damage which cannot be reversed by current medical technology. Whether or not the damage inflicted by current methods can ever be reversed depends both on the level of damage and the ultimate limits of future medical technology. The failure to reverse freezing injury with current methods does not imply that it can never be reversed in the future, just as the inability to build a personal computer in 1890 did not imply that such machines would never be economically built. This paper considers the limits of what medical technology should eventually be able to achieve (based on the currently understood laws of chemistry and physics) and the kinds of damage caused by current methods of freezing. It then considers whether methods of repairing the kinds of damage caused by current suspension techniques are likely to be achieved in the future.

Perhaps the most important question in evaluating this option is its technical feasibility: will it work?

Given the remarkable progress of science during the past few centuries it is difficult to dismiss cryonics out of hand. The structure of DNA was unknown prior to 1953; the chemical (rather than "vitalistic") nature of living beings was not appreciated until early in the 20th century; it was not until 1864 that spontaneous generation was put to rest by Louis Pasteur, who demonstrated that no organisms emerged from heat-sterilized growth medium kept in sealed flasks; and Sir Isaac Newton's Principia established the laws of motion in 1687, just over 300 years ago. If progress of the same magnitude occurs in the next few centuries, then it becomes difficult to argue that the repair of frozen tissue is inherently and forever infeasible.

Hesitation to dismiss cryonics is not a ringing endorsement and still leaves the basic question in considerable doubt. Perhaps a closer consideration of how future technologies might be applied to the repair of frozen tissue will let us draw stronger conclusions -- in one direction or the other. Ultimately, cryonics will either (a) work or (b) fail to work. It would seem useful to know in advance which of these two outcomes to expect. If it can be ruled out as infeasible, then we need not waste further time on it. If it seems likely that it will be technically feasible, then a number of nontechnical issues should be addressed in order to obtain a good probability of overall success.

The reader interested in a general introduction to cryonics is referred to other sources[23, 24, 80]. Here, we focus on technical feasibility.

While many isolated tissues (and a few particularly hardy organs) have been successfully cooled to the temperature of liquid nitrogen and rewarmed[59], further successes have proven elusive. While there is no particular reason to believe that a cure for freezing damage would violate any laws of physics (or is otherwise obviously infeasible), it is likely that the damage done by freezing is beyond the self-repair and recovery capabilities of the tissue itself. This does not imply that the damage cannot be repaired, only that significant elements of the repair process would have to be provided from an external source. In deciding whether such externally provided repair will (or will not) eventually prove feasible, we must keep in mind that such repair techniques can quite literally take advantage of scientific advances made during the next few centuries. Forecasting the capabilities of future technologies is therefore an integral component of determining the feasibility of cryonics. Such a forecast should, in principle, be feasible. The laws of physics and chemistry as they apply to biological structures are well understood and well defined. Whether the repair of frozen tissue will (or will not) eventually prove feasible within the framework defined by those laws is a question which we should be able to answer based on what is known today.

Current research (outlined below) supports the idea that we will eventually be able to examine and manipulate structures molecule by molecule and even atom by atom. Such a technical capability has very clear implications for the kinds of damage that can (and cannot) be repaired. The most powerful repair capabilities that should eventually be possible can be defined with remarkable clarity. The question we wish to answer is conceptually straightforward: will the most powerful repair capability that is likely to be developed in the long run (perhaps over a few centuries) be adequate to repair tissue that is frozen using the best available current methods?[note 2] Eigler and Schweizer[49] have already developed the capability "... to fabricate rudimentary structures of our own design, atom by atom." Eigler said[129], "...by the time I'm ready to kick the bucket, we might be able to store enough information on my exact physical makeup that someday we'll be able to reassemble me, atom by atom."

The general purpose ability to manipulate structures with atomic precision and low cost is often called nanotechnology (also called molecular engineering, molecular manufacturing, molecular nanotechnology , etc.). There is widespread belief that such a capability will eventually be developed [1, 2, 3, 4, 7, 8, 10, 19, 41, 47, 49, 83, 84, 85, 106, 107, 108, 116, 117, 118, 119, 121, 122] though exactly how long it will take is unclear. The long storage times possible with cryonic suspension make the precise development time of such technologies noncritical. Development any time during the next few centuries would be sufficient to save the lives of those suspended with current technology.

In this paper, we give a brief introduction to nanotechnology and then clarify the technical issues involved in applying it in the conceptually simplest and most powerful fashion to the repair of frozen tissue.

NANOTECHNOLOGY

This concept is receiving increasing attention in the research community. There have been two international research conferences directly on molecular manufacturing [83, 84, 116, 121] as well as a broad range of conferences on related subjects. Science [47, page 26] said "The ability to design and manufacture devices that are only tens or hundreds of atoms across promises rich rewards in electronics, catalysis, and materials. The scientific rewards should be just as great, as researchers approach an ultimate level of control -- assembling matter one atom at a time." "Within the decade, [John] Foster [at IBM Almaden] or some other scientist is likely to learn how to piece together atoms and molecules one at a time using the STM [Scanning Tunneling Microscope]."

Eigler and Schweizer[49] at IBM reported on "...the use of the STM at low temperatures (4 K) to position individual xenon atoms on a single-crystal nickel surface with atomic precision. This capacity has allowed us to fabricate rudimentary structures of our own design, atom by atom. The processes we describe are in principle applicable to molecules also. In view of the device-like characteristics reported for single atoms on surfaces [omitted references], the possibilities for perhaps the ultimate in device miniaturization are evident."

J. A. Armstrong, IBM Chief Scientist and Vice President for Science and Technology[106] said "I believe that nanoscience and nanotechnology will be central to the next epoch of the information age, and will be as revolutionary as science and technology at the micron scale have been since the early '70's.... Indeed, we will have the ability to make electronic and mechanical devices atom-by-atom when that is appropriate to the job at hand."

The New York Times said[107]: "Scientists are beginning to gain the ability to manipulate matter by its most basic components --- molecule by molecule and even atom by atom." "That ability, while now very crude, might one day allow people to build almost unimaginably small electronic circuits and machines, producing, for example, a super computer invisible to the naked eye. Some futurists even imagine building tiny robots that could travel through the body performing surgery on damaged cells."

Drexler[1,10,19,41, 85] has proposed the assembler, a small device resembling an industrial robot which would be capable of holding and positioning reactive compounds in order to control the precise location at which chemical reactions take place. This general approach should allow the construction of large atomically precise objects by a sequence of precisely controlled chemical reactions.

The best technical discussion of nanotechnology has recently been provided by Drexler[ 85].

Ribosomes

The instructions that the ribosome follows in building a protein are provided by mRNA (messenger RNA). This is a polymer formed from the 4 bases adenine, cytosine, guanine, and uracil. A sequence of several hundred to a few thousand such bases codes for a specific protein. The ribosome "reads" this "control tape" sequentially, and acts on the directions it provides.

Assemblers

Calculations indicate that an assembler need not inherently be very large. Enzymes "typically" weigh about 10^{^5} amu (atomic mass units [note 3]), while the ribosome itself is about 3 x 10^{^6} amu[14]. The smallest assembler might be a factor of ten or so larger than a ribosome. Current design ideas for an assembler are somewhat larger than this: cylindrical "arms" about 100 nanometers in length and 30 nanometers in diameter, rotary joints to allow arbitrary positioning of the tip of the arm, and a worst-case positional accuracy at the tip of perhaps 0.1 to 0.2 nanometers, even in the presence of thermal noise[ 85]. Even a solid block of diamond as large as such an arm weighs only sixteen million amu, so we can safely conclude that a hollow arm of such dimensions would weigh less. Six such arms would weigh less than 10^{^8} amu.

Molecular Computers

An assembler might have a kilobyte of high speed (rod-logic based) RAM, (similar to the amount of RAM used in a modern one-chip computer) and 100 kilobytes of slower but more dense "tape" storage -- this tape storage would have a mass of 10^{^8} amu or less (roughly 10 atoms per bit -- see below). Some additional mass will be used for communications (sending and receiving signals from other computers) and power. In addition, there will probably be a "toolkit" of interchangeable tips that can be placed at the ends of the assembler's arms. When everything is added up a small assembler, with arms, computer, "toolkit," etc. should weigh less than 10^{^9} amu.

E. coli (a common bacterium) weighs about 10^{^12} amu[14, page 123]. Thus, an assembler should be much larger than a ribosome, but much smaller than a bacterium.

Self Replicating Systems

Further work on self-replicating systems was done by NASA in 1980 in a report that considered the feasibility of implementing a self-replicating lunar manufacturing facility with conventional technology[48]. One of their conclusions was that "The theoretical concept of machine duplication is well developed. There are several alternative strategies by which machine self-replication can be carried out in a practical engineering setting." They estimated it would require 20 years (and many billions of dollars) to develop such a system. While they were considering the design of a macroscopic self-replicating system (the proposed "seed" was 100 tons) many of the concepts and problems involved in such systems are similar regardless of size.

Positional Chemistry

A large atomically precise structure, however, can be viewed as simply a collection of small atomically precise objects which are then linked together. To build a truly broad range of large atomically precise objects requires the ability to create highly specific positionally controlled bonds. A variety of highly flexible synthetic techniques have been considered by Drexler [ 85]. We shall describe two such methods here to give the reader a feeling for the kind of methods that will eventually be feasible.

We assume that positional control is available and that all reactions take place in a hard vacuum. The use of a hard vacuum allows highly reactive intermediate structures to be used, e.g., a variety of radicals with one or more dangling bonds. Because the intermediates are in a vacuum, and because their position is controlled (as opposed to solutions, where the position and orientation of a molecule are largely random), such radicals will not react with the wrong thing for the very simple reason that they will not come into contact with the wrong thing.

It is difficult to maintain biological structures in a hard vacuum at room temperature because of water vapor and the vapor of other small compounds. By sufficiently lowering the temperature, however, it is possible to reduce the vapor pressure to effectively 0.

Normal solution-based chemistry offers a smaller range of controlled synthetic possibilities. For example, highly reactive compounds in solution will promptly react with the solution. In addition, because positional control is not provided, compounds randomly collide with other compounds. Any reactive compound will collide randomly and react randomly with anything available (including itself). Solution-based chemistry requires extremely careful selection of compounds that are reactive enough to participate in the desired reaction, but sufficiently non-reactive that they do not accidentally participate in undesired side reactions. Synthesis under these conditions is somewhat like placing the parts of a radio into a box, shaking, and pulling out an assembled radio. The ability of chemists to synthesize what they want under these conditions is amazing.

Much of current solution-based chemical synthesis is devoted to preventing unwanted reactions. With assembler-based synthesis, such prevention is a virtually free by-product of positional control.

To illustrate positional synthesis in vacuum somewhat more concretely, let us suppose we wish to bond two compounds, A and B. As a first step, we could utilize positional control to selectively abstract a specific hydrogen atom from compound A. To do this, we would employ a radical that had two spatially distinct regions: one region would have a high affinity for hydrogen while the other region could be built into a larger "tip" structure that would be subject to positional control. A simple example would be the 1-propynyl radical, which consists of three co-linear carbon atoms and three hydrogen atoms bonded to the sp3 carbon at the "base" end. The radical carbon at the radical end is triply bonded to the middle carbon, which in turn is singly bonded to the base carbon. In a real abstraction tool, the base carbon would be bonded to other carbon atoms in a larger diamondoid structure which would provide positional control, and the tip might be further stabilized by a surrounding "collar" of unreactive atoms attached near the base that would limit lateral motions of the reactive tip.

The affinity of this structure for hydrogen is quite high. Propyne (the same structure but with a hydrogen atom bonded to the "radical" carbon) has a hydrogen-carbon bond dissociation energy in the vicinity of 132 kilocalories per mole. As a consequence, a hydrogen atom will prefer being bonded to the 1-propynyl hydrogen abstraction tool in preference to being bonded to almost any other structure. By positioning the hydrogen abstraction tool over a specific hydrogen atom on compound A, we can perform a site specific hydrogen abstraction reaction. This requires positional accuracy of roughly a bond length (to prevent abstraction of an adjacent hydrogen). Quantum chemical analysis of this reaction by Musgrave et. al.[108] show that the activation energy for this reaction is low, and that for the abstraction of hydrogen from the hydrogenated diamond (111) surface (modeled by isobutane) the barrier is very likely zero.

Having once abstracted a specific hydrogen atom from compound A, we can repeat the process for compound B. We can now join compound A to compound B by positioning the two compounds so that the two dangling bonds are adjacent to each other, and allowing them to bond.

This illustrates a reaction using a single radical. With positional control, we could also use two radicals simultaneously to achieve a specific objective. Suppose, for example, that two atoms A1 and A2 which are part of some larger molecule are bonded to each other. If we were to position the two radicals X1 and X2 adjacent to A1 and A2, respectively, then a bonding structure of much lower free energy would be one in which the A1-A2 bond was broken, and two new bonds A1-X1 and A2-X2 were formed. Because this reaction involves breaking one bond and making two bonds (i.e., the reaction product is not a radical and is chemically stable) the exact nature of the radicals is not critical. Breaking one bond to form two bonds is a favored reaction for a wide range of cases. Thus, the positional control of two radicals can be used to break any of a wide range of bonds.

A range of other reactions involving a variety of reactive intermediate compounds (carbenes are among the more interesting ones) are proposed in [85], along with the results of semi-empirical and ab initio quantum calculations and the available experimental evidence.

Another general principle that can be employed with positional synthesis is the controlled use of force. Activation energy, normally provided by thermal energy in conventional chemistry, can also be provided by mechanical means. Pressures of 1.7 megabars have been achieved experimentally in macroscopic systems[30]. At the molecular level such pressure corresponds to forces that are a large fraction of the force required to break a chemical bond. A molecular vise made of hard diamond-like material with a cavity designed with the same precision as the reactive site of an enzyme can provide activation energy by the extremely precise application of force, thus causing a highly specific reaction between two compounds.

To achieve the low activation energy needed in reactions involving radicals requires little force, allowing a wider range of reactions to be caused by simpler devices (e.g., devices that are able to generate only small force). Further analysis is provided in [85].

Feynman said: "The problems of chemistry and biology can be greatly helped if our ability to see what we are doing, and to do things on an atomic level, is ultimately developed -- a development which I think cannot be avoided." Drexler has provided the substantive analysis required before this objective can be turned into a reality. We are nearing an era when we will be able to build virtually any structure that is specified in atomic detail and which is consistent with the laws of chemistry and physics. This has substantial implications for future medical technologies and capabilities.

Repair Devices

A single repair device of the kind described will not, by itself, have sufficient memory to store the programs required to perform all the repairs. However, if it is connected to a network (in the same way that current computers can be connected into a local area network) then a single large "file server" can provide the needed information for all the repair devices on the network. The file server can be dedicated to storing information: all the software and data that the repair devices will need. Almost the entire mass of the file server can be dedicated to storage, it can service many repair devices, and can be many times the size of one device without greatly increasing system size. Combining these advantages implies the file server will have ample storage to hold whatever programs might be required during the course of repair. In a similar fashion, if further computational resources are required they can be provided by "large" compute servers located on the network.

Cost

One consequence of the existence of assemblers is that they are cheap. Because an assembler can be programmed to build almost any structure, it can in particular be programmed to build another assembler. Thus, self reproducing assemblers should be feasible and in consequence the manufacturing costs of assemblers would be primarily the cost of the raw materials and energy required in their construction. Eventually (after amortization of possibly quite high development costs), the price of assemblers (and of the objects they build) should be no higher than the price of other complex structures made by self-replicating systems. Potatoes -- which have a staggering design complexity involving tens of thousands of different genes and different proteins directed by many megabits of genetic information -- cost well under a dollar per pound.

DESCRIBING THE BRAIN AT THE MOLECULAR LEVEL

The brain, like all the familiar matter in the world around us, is made of atoms. It is the spatial arrangement of these atoms that distinguishes an arm from a leg, the head from the heart, and sickness from health. This view of the brain is the framework for our problem, and it is within this framework that we must work. Our problem, broadly stated, is that the atoms in a frozen brain are in the wrong places. We must put them back where they belong (with perhaps some minor additions and removals, as well as just rearrangements) if we expect to restore the natural functions of this most wonderful organ.

In principle, the most that we could usefully know about the frozen brain would be the coordinates of each and every atom in it (though confer note 5 ). This knowledge would put us in the best possible position to determine where each and every atom should go. This knowledge, combined with a technology that allowed us to rearrange atomic structure in virtually any fashion consistent with the laws of chemistry and physics, would clearly let us restore the frozen structure to a fully functional and healthy state.

In short, we must answer three questions:

1. Where are the atoms?
2. Where should they go?
3. How do we move them from where they are to where they should be?

Rather than directly consider these questions at once, we shall first consider a simpler problem: how would we go about describing the position of every atom if somehow this information was known to us? The answer to this question will let us better understand the harder questions.

Other work which considers the information required to describe a human being exists[127, 128].

How Many Bits to Describe One Atom

Thus, if we could store 100 bits of information for every atom in the brain, we could fully describe its structure in as exacting and precise a manner as we could possibly need. (Dancoff and Quastler[128], using a somewhat better encoding scheme, say that 24.5 bits per atoms should suffice). A memory device of this capacity should be quite literally possible. To quote Feynman[4]: "Suppose, to be conservative, that a bit of information is going to require a little cube of atoms 5 x 5 x 5 -- that is 125 atoms." This is indeed conservative. Single stranded DNA already stores a single bit in about 16 atoms (excluding the water that it's in). It seems likely we can reduce this to only a few atoms[1]. The work at IBM[49] suggests a rather obvious way in which the presence or absence of a single atom could be used to encode a single bit of information (although some sort of structure for the atom to rest upon and some method of sensing the presence or absence of the atom will still be required, so we would actually need more than one atom per bit in this case). If we conservatively assume that the laws of chemistry inherently require 10 atoms to store a single bit of information, we still find that the 100 bits required to describe a single atom in the brain can be represented by about 1,000 atoms. Put another way, the location of every atom in a frozen structure is (in a sense) already encoded in that structure in an analog format. If we convert from this analog encoding to a digital encoding, we will increase the space required to store the same amount of information. That is, an atom in three-space encodes its own position in the analog value of its three spatial coordinates. If we convert this spatial information from its analog format to a digital format, we inflate the number of atoms we need by perhaps as much as 1,000. If we digitally encoded the location of every atom in the brain, we would need 1,000 times as many atoms to hold this encoded data as there are atoms in the brain. This means we would require roughly 1,000 times the volume. The brain is somewhat over one cubic decimeter, so it would require somewhat over one cubic meter of material to encode the location of each and every atom in the brain in a digital format suitable for examination and modification by a computer.

While this much memory is remarkable by today's standards, its construction clearly does not violate any laws of physics or chemistry. That is, it should literally be possible to store a digital description of each and every atom in the brain in a memory device that we will eventually be able to build.

How Many Bits to Describe a Molecule

As the molecule we are describing gets larger and larger, the savings in storage gets bigger and bigger. A whole protein molecule will still require only 150 bits to describe, even though it is made of thousands of atoms. The canonical position of every atom in the molecule is specified once the type of the molecule (which occupies a mere 20 bits) is given. A large molecule might adopt many configurations, so it might at first seem that we'd require many more bits to describe it. However, biological macromolecules typically assume one favored configuration rather than a random configuration, and it is this favored configuration that we will describe [note 6].

We can do even better: the molecules in the brain are packed in next to each other. Having once described the position of one, we can describe the position of the next molecule as being such-and-such a distance from the first. If we assume that two adjacent molecules are within 10 nanometers of each other (a reasonable assumption) then we need only store 10 bits of "delta X," 10 bits of "delta Y," and 10 bits of "delta Z" rather than 33 bits of X, 33 bits of Y, and 33 bits of Z. This means our molecule can be described in only 10+10+10+20+30 or 80 bits.

We can compress this further by using various other clever stratagems (50 bits or less is quite achievable), but the essential point should be clear. We are interested in molecules, and describing a molecule takes fewer bits than describing an atom.

Do We Really Need to Describe Each Molecule?

While this reduces our storage requirements quite a bit, we could go much further. Instead of describing molecules, we could describe entire sub-cellular organelles. It seems excessive to describe a mitochondrion by describing each and every molecule in it. It would be sufficient simply to note the location and perhaps the size of the mitochondrion, for all mitochondria perform the same function: they produce energy for the cell. While there are indeed minor differences from mitochondrion to mitochondrion, these differences don't matter much and could reasonably be neglected.

We could go still further, and describe an entire cell with only a general description of the function it performs: this nerve cell has synapses of a certain type with that other cell, it has a certain shape, and so on. We might even describe groups of cells in terms of their function: this group of cells in the retina performs a "center surround" computation, while that group of cells performs edge enhancement. Cherniak[115] said: "On the usual assumption that the synapse is the necessary substrate of memory, supposing very roughly that (given anatomical and physiological "noise") each synapse encodes about one binary bit of information, and a thousand synapses per neuron are available for this task: 10^{^10} cortical neurons x 10^{^3} synapses = 10^{^13} bits of arbitrary information (1.25 terabytes) that could be stored in the cerebral cortex."

How Many Bits Do We Really Need?

This kind of logic can be continued, but where does it stop? What is the most compact description which captures all the essential information? While many minor details of neural structure are irrelevant, our memories clearly matter. Any method of describing the human brain which resulted in loss of long term memory has rather clearly gone too far. When we examine this quantitatively, we find that preserving the information in our long term memory might require as little as 10^{^9} bits (somewhat over 100 megabytes)[37]. We can say rather confidently that it will take at least this much information to adequately describe an individual brain. The gap between this lower bound and the molecule-by-molecule upper bound is rather large, and it is not immediately obvious where in this range the true answer falls. We shall not attempt to answer this question, but will instead (conservatively) simply adopt the upper bound.

CRITERIA OF DEATH

death \'deth\ n [ME deeth, fr. OE death; akin to ON dauthi death, deyja to die -- more at DIE] 1: a permanent cessation of all vital functions : the end of life
Webster's New Collegiate Dictionary

Determining when "a permanent cessation of all vital functions" has occurred is not easy. Historically, premature declarations of death and subsequent burial alive have been a major problem. In the seventh century, Celsus wrote "... Democritus, a man of well merited celebrity, has asserted that there are in reality, no characteristics of death sufficiently certain for physicians to rely upon."[87, page 166].

Montgomery, reporting on the evacuation of the Fort Randall Cemetery, states that nearly two percent of those exhumed were buried alive[87].

Many people in the nineteenth century, alarmed by the prevalence of premature burial, requested, as part of the last offices, that wounds or mutilations be made to assure that they would not awaken ... embalming received a considerable impetus from the fear of premature burial.

New Criteria

Each new medical advance forces a reexamination and possible change of the existing ad hoc criteria. The criteria used by the clinician today to determine "death" are dramatically different from the criteria used 100 years ago, and have changed more subtly but no less surely in the last decade [note 7]. It seems almost inevitable that the criteria used 100 years from now will differ dramatically from the criteria commonly employed today.

These ever shifting criteria for "death" raise an obvious question: is there a definition which will not change with advances in technology? A definition which does have a theoretical underpinning and is not dependent on the technology of the day?

The answer arises from the confluence and synthesis of many lines of work, ranging from information theory, neuroscience, physics, biochemistry and computer science to the philosophy of the mind and the evolving criteria historically used to define death.

When someone has suffered a loss of memory or mental function, we often say they "aren't themselves." As the loss becomes more serious and all higher mental functions are lost, we begin to use terms like "persistent vegetative state." While we will often refrain from declaring such an individual "dead," this hesitation does not usually arise because we view their present state as "alive" but because there is still hope of recovery to a healthy state with memory and personality intact. From a physical point of view we believe there is a chance that their memories and personalities are still present within the physical structure of the brain, even though their behavior does not provide direct evidence for this. If we could reliably determine that the physical structures encoding memory and personality had in fact been destroyed, then we would abandon hope and declare the person dead.

The Information Theoretic Criterion of Death

Considerations like this lead to the information theoretic criterion of death [note 8]. A person is dead according to the information theoretic criterion if their memories, personality, hopes, dreams, etc. have been destroyed in the information theoretic sense. That is, if the structures in the brain that encode memory and personality have been so disrupted that it is no longer possible in principle to restore them to an appropriate functional state then the person is dead. If the structures that encode memory and personality are sufficiently intact that inference of the memory and personality are feasible in principle, and therefore restoration to an appropriate functional state is likewise feasible in principle, then the person is not dead.

A simple example from computer technology is in order. If a computer is fully functional then its memory and "personality" are completely intact. If it fell out the seventh floor window to the concrete below, it would rapidly cease to function. However, its memory and "personality" would still be present in the pattern of magnetizations on the disk. With sufficient effort, we could completely repair the computer with its memory and "personality" intact [note 9].

In a similar fashion, as long as the structures that encode the memory and personality of a human being have not been irretrievably "erased" (to use computer jargon) then restoration to a fully functional state with memory and personality intact is in principle feasible. Any technology independent definition of "death" should conclude that such a person is not dead, for a sufficiently advanced technology could restore the person to a healthy state.

On the flip side of the coin, if the structures encoding memory and personality have suffered sufficient damage to obliterate them beyond recognition, then death by the information theoretic criterion has occurred. An effective method of insuring such destruction is to burn the structure and stir the ashes. This is commonly employed to insure the destruction of classified documents. Under the name of "cremation" it is also employed on human beings and is sufficient to insure that death by the information theoretic criterion takes place.

More Exotic Approaches

The ethicist and prolific author Robert Veatch said, in Death, Dying, and the Biological Revolution, "An `artificial brain' is not possible at present, but a walking, talking, thinking individual who had one would certainly be considered living."[15, page 23].

The noted philosopher of consciousness Paul Churchland said, in Matter and Consciousness, "If machines do come to simulate all of our internal cognitive activities, to the last computational detail, to deny them the status of genuine persons would be nothing but a new form of racism."[12, page 120].

Hans Moravec, renowned roboticist and Director of the Mobile Robot Lab at Carnegie Mellon said, "Body-identity assumes that a person is defined by the stuff of which a human body is made. Only by maintaining continuity of body stuff can we preserve an individual person. Pattern-identity, conversely, defines the essence of a person, say myself, as the pattern and the process going on in my head and body, not the machinery supporting that process. If the process is preserved, I am preserved. The rest is mere jelly."[50, page 117].

We'll Use the Conservative Approach

Another issue is not so much philosophical as emotional. Major surgery is not a pretty sight. There are few people who can watch a surgeon cut through living tissue with equanimity. In a heart transplant, for example, surgeons cut open the chest of a dying patient to rip out their dying heart, cut open a fresh cadaver to seize its still-beating heart, and then stitch the cadaver's heart into the dying patients chest. Despite this (which would have been condemned in the middle ages as the blackest of black magic), we cheer the patient's return to health and are thankful that we live in an era when medicine can save lives that were formerly lost.

The mechanics of examining and repairing the human brain, possibly down to the level of individual molecules, might not be the best topic for after dinner conversation. While the details will vary depending on the specific method used, this could also be described by lurid language that failed to capture the central issue: the restoration to full health of a human being.

A final issue that should be addressed is that of changes introduced by the process of restoration itself. The exact nature and extent of these changes will vary with the specific method. Current surgical techniques, for example, result in substantial tissue changes. Scarring, permanent implants, prosthetics, etc. are among the more benign outcomes. In general, methods based on a sophisticated ability to rearrange atomic structure should result in minimal undesired alterations to the tissue.

"Minimal changes" does not mean "no changes." A modest amount of change in molecular structure, whatever technique is used, is both unavoidable and insignificant. The molecular structure of the human brain is in a constant state of change during life -- molecules are synthesized, utilized, and catabolized in a continuous cycle. Cells continuously undergo slight changes in morphology. Cells also make small errors in building their own parts. For example, ribosomes make errors when they build proteins. About one amino acid in every 10,000 added to a growing polypeptide chain by a ribosome is incorrect[14, page 383]. Changes and errors of a similar magnitude introduced by the process of restoration can reasonably be neglected.

Does the Information Theoretic Criterion Matter?

In this one instance, we must ask not whether the person is dead by today's (clearly technology dependent) criteria, but whether the person is dead by all future criteria. In short, we must ask whether death by the information theoretic criterion has taken place. If it has not, then cryonic suspension is a reasonable (and indeed life saving) course of action.

Experimental Proof or Disproof of Cryonics

The scientifically correct experiment to verify that cryonics works (or demonstrate that it does not work) is quite easy to describe:

1. Select N experimental subjects.
2. Freeze them.
3. Wait 100 years.
4. See if the technology available 100 years from now can (or cannot) cure them.

This kind of problem is not entirely unique to cryonics. A new AIDS treatment might undergo clinical trials lasting a few years. The ethical dilemma posed by the terminally ill AIDS patient who might be assisted by the experimental treatment is well known. If the AIDS patient is given the treatment prior to completion of the clinical trials, it is possible that his situation could be made significantly worse. On the other hand, to deny a potentially life saving treatment to someone who will soon die anyway is ethically untenable.

In the case of cryonics this is not an interim dilemma pending the (near term) outcome of clinical trials. It is a dilemma inherent in the nature of the proposal. Clinical trials, the bulwark of modern medical practice, are useless in resolving the effectiveness of cryonics in a timely fashion.

Further, cryonics (virtually by definition) is a procedure used only when the patient has exhausted all other available options. In current practice the patient is suspended after legal death: the fear that the treatment might prove worse than the disease is absent. Of course, suspension of the terminally ill patient somewhat before legal death has significant advantages. A patient suffering from a brain tumor might view suspension following the obliteration of his brain as significantly less desirable than suspension prior to such obliteration, even if the suspension occurred at a point in time when the patient was legally "alive."

In such a case, it is inappropriate to disregard or override the patient's own wishes. To quote the American College of Physicians Ethics Manual, "Each patient is a free agent entitled to full explanation and full decision-making authority with regard to his medical care. John Stuart Mill expressed it as: `Over himself, his own body and mind, the individual is sovereign.' The legal counterpart of patient autonomy is self-determination. Both principles deny legitimacy to paternalism by stating unequivocally that, in the last analysis, the patient determines what is right for him." "If the [terminally ill] patient is a mentally competent adult, he has the legal right to accept or refuse any form of treatment, and his wishes must be recognized and honored by his physician."[92]

If clinical trials cannot provide us with an answer, are there any other methods of evaluating the proposal? Can we do more than say that (a) cryonic suspension can do no harm (in keeping with the Hippocratic oath), and (b) it has some difficult-to-define chance of doing good?

Failure Criteria

Cryonics will fail if:

1. Information theoretic death occurs prior to reaching liquid nitrogen temperature [note 11].
2. Repair technology that is feasible in principle is never developed and applied in practice, even after the passage of centuries.

The second failure criterion is considered in the later sections on technical issues, which discuss in more detail how future technologies might be applied to the repair of frozen tissue.

As the reader will readily appreciate, the following reviews will consider only the most salient points that are of the greatest importance in determining overall feasibility. They are necessarily too short to consider the topics in anything like full detail, but should provide sufficient information to give the reader an overview of the relevant issues. References to further reading are provided throughout [note 12].

FREEZING DAMAGE

While cooling tissue to around 0 degrees C creates a number of problems, the ability to cool mammals to this temperature or even slightly below (with no ice formation) using current methods followed by subsequent complete recovery[61, 62] shows that this problem can be controlled and is unlikely to cause information theoretic death. We will, therefore, ignore the problems caused by such cooling. This problem is discussed in [5] and elsewhere.

Further, some "freezing" damage in fact occurs upon re- warming. Current work supports this idea because the precise method used to re-warm tissue can strongly affect the success or failure of present experiments even when freezing conditions are identical[5, 6]. If we presume that future repair methods avoid the step of re-warming the tissue prior to analysis and instead analyze the tissue directly in the frozen state then this source of damage will be eliminated. Several current methods can be used to distinguish between damage that occurs during freezing and damage that occurs while thawing. At present, it seems likely that some damage occurs during each process. While significant damage does occur during slow freezing, it does not induce structural changes which obliterate the cell.

Present Day Successes

Fractures

Fractures that occur below the glass transition temperature result in very little information loss. While dramatic, this damage is unlikely to cause or contribute to information theoretic death.

Ice

Extracellular ice formation causes an increase in the concentration of the extra-cellular solute, e.g., the chemicals in the extracellular liquid are increased in concentration by the decrease in available water. The immediate effect of this increased extracellular concentration is to draw water out of the cells by osmosis. Thus, freezing dehydrates cells.

Damage can be caused by the extracellular ice, by the increased concentration of solute, or by the reduced temperature itself. All three mechanisms can play a role under appropriate conditions.

The damage caused by extracellular ice formation depends largely on the fraction of the initial liquid volume that is converted to ice[6, 57]. (The initial liquid volume might include a significant amount of cryoprotectant as well as water). When the fraction of the liquid volume converted to ice is small, damage is often reversible even by current techniques. In many cases, conversion of significantly more than 40% of the liquid volume to ice is damaging[70, page 134; 71]. The brain is more resistant to such injury: conversion of up to 60% of the liquid volume in the brain to ice is associated with recovery of neuronal function[58, 62, 66, 82]. Storey and Storey said "If the cell volume falls below a critical minimum, then the bilayer of phospholipids in the membrane becomes so greatly compressed that its structure breaks down. Membrane transport functions cannot be maintained, and breaks in the membrane spill cell contents and provide a gate for ice to propagate into the cell. Most freeze-tolerant animals reach the critical minimum cell volume when about 65 percent of total body water is sequestered as ice."[57].

Appropriate treatment with cryoprotectants (in particular glycerol) prior to freezing will keep 40% or more of the liquid volume from being converted to ice even at liquid nitrogen temperatures.

Fahy has said "All of the postulated problems in cryobiology -- cell packing [omitted reference], channel size constraints [omitted reference], optimal cooling rate differences for mixed cell populations [omitted reference], osmotically mediated injury[omitted references], and the rest -- can be solved in principle by the selection of a sufficiently high concentration of cryoprotectant prior to freezing. In the extreme case, all ice formation could be suppressed completely by using a concentration of agent sufficient to ensure vitrification of the biological system in question [omitted reference]"[73]. Unfortunately, a concentration of cryoprotectant sufficiently high to protect the system from all freezing injury would itself be injurious[73]. It should be possible to trade the mechanical injury caused by ice formation for the biochemical injury caused by the cryoprotectant, which is probably advantageous. Current suspension protocols at Alcor call for the introduction of greater than 6 molar glycerol. Both venous and arterial glycerol concentrations have exceeded 6 molar in several recent suspensions. If this concentration of cryoprotectant is also reaching the tissues, it should keep over 60% of the initial liquid volume from being converted to ice at liquid nitrogen temperatures [note 14].

Concentration Effects

Denaturing

Intracellular Freezing

Intracellular freezing is largely irrelevant to cryonic suspensions because of the slow freezing rates dictated by the large mass of tissue being frozen. Such freezing rates are too slow for intracellular freezing to occur except when membrane rupture allows extracellular ice to penetrate the intracellular region. If the membrane does fail, one would expect the interior of the cell to "flash."

Loss of Information versus Loss of Function

Spontaneous recovery of function following freezing to liquid nitrogen temperatures using the best currently available techniques appears unlikely for mammalian organs, including the brain. Despite this, the level of structural preservation can be quite good. The complexity of the systems that have been successfully frozen and rewarmed is remarkable, and supports the claim that good structural preservation is often achieved. The mechanisms of damage that have been postulated in the literature are sufficiently subtle that information loss is likely to be small; that is, death by the information theoretic criterion is unlikely to have occurred. Further research aimed specifically at addressing this issue is needed.

ISCHEMIC INJURY AND PRESUSPENSION INJURY

Broadly speaking, the structure of the human brain remains intact for several hours or more following the cessation of blood flow, or ischemia. The tissue changes that occur subsequent to ischemia have been well studied. There have also been studies of the "postmortem" changes that occur in tissue. Perhaps the most interesting of these studies was conducted by Kalimo et. al.[65].

"Postmortem" Changes in the Human Brain

Effects of postmortem delay. Some brain functions are damaged irreversibly within minutes of the cessation of blood flow to the tissue. This led to the widespread belief that it would be impossible to isolate metabolically active and responsive preparations very long after death and use them to study neurotransmission. However, this is a misconception; many groups have successfully obtained functional preparations from normal (Table 1) [not present in this article] and pathological (Table 2) [not present in this article] human brain tissue from autopsies carried out up to 24 h or more postmortem. This is perhaps less surprising when the stability of enzymes, receptors, and nucleic acids is taken into consideration (see Hardy and Dodd, 1983 [reference 123 in this article]). With very few exceptions, the brain retains the metabolic machinery to reconstitute tissue metabolite and neurotransmitter pools. It also appears that sufficient structural integrity is retained to allow the various tissue compartments to remain relatively intact and distinct.

Experiments with both animal and human brain have shown that viable preparations can be isolated routinely up to at least 24 h postmortem, a time scale within which a sufficient number of autopsies is carried out to allow extensive neurochemical studies. When the human subject has died suddenly (see below) [not in this article], such preparations exhibit the same range of characteristics as preparations made from fresh animal tissue, or from fresh human tissue obtained at biopsy or neurosurgery. Thus incubated synaptosomes and brain slices from postmortem human brain respire, accumulate tissue potassium, maintain membrane potentials, release neurotransmitters in a calcium-dependent fashion, and possess active, sodium - dependent uptake systems (see Table 1 for references [not in this article]). Electron microscopic examination of synaptosome preparations from postmortem human brain showed them to be only slightly less pure than preparations from fresh tissue, although some degree of damage is evident (Hardy et al., 1982 [not in this article]).

As an aside, the vascular perfusion of chemical fixatives to improve stability of tissue structures prior to perfusion with cryoprotectants and subsequent storage in liquid nitrogen would seem to offer significant advantages. The main issue that would require resolution prior to such use is the risk that fixation might obstruct circulation, thus impeding subsequent perfusion with cryoprotectants. Other than this risk, the use of chemical fixatives (such as aldehydes and in particular glutaraldehyde) would reliably improve structural preservation and would be effective at halting almost all deterioration within minutes of perfusion[67]. The utility of chemical preservation has been discussed by Drexler[1] and by Olson[90], among others.

Ischemia

Ischemic changes do not appear to result in any damage that would prevent repair (e.g., changes that would result in significant loss of information about structure) for at least a few hours. Temporary functional recovery has been demonstrated in optimal situations after as long as 60 minutes of total ischemia[93, 94, 95]. Hossmann, for example, reported results on 143 cats subjected to one hour of normothermic global brain ischemia[97]. "Body temperature was maintained at 36 degrees to 37 degrees C with a heating pad. ... Completeness of ischemia was tested by injecting 133Xe into the innominate artery immediately before vascular occlusion and monitoring the absence of decay of radioactivity from the head during ischemia, using external scintillation detectors. ... In 50% of the animals, even major spontaneous EEG activity returned after ischemia.... One cat survived for 1 yr after one hour of normothermic cerebrocirculatory arrest with no electrophysiologic deficit and with only minor neurologic and morphologic disturbances." Functional recovery is a more stringent criterion than the more relaxed information theoretic criterion, which merely requires adequate structural preservation to allow inference about the pre-existing structure. Reliable identification of the various cellular structures is possible hours (and sometimes even days) later. Detailed descriptions of ischemia and its time course[72, page 209 et sequitur] also clearly show that cooling substantially slows the rate of deterioration. Thus, even moderate cooling "postmortem" slows deterioration significantly.

Lysosomes

Kalimo et. al.[74] said "It is noteworthy that after 120 min of complete blood deprivation we saw no evidence of membrane lysosomal breakdown, an observation which has also been reported in studies of in vitro lethal cell injury[omitted references], and in regional cerebral ischemia[omitted references]."

Hawkins et. al.[75] said "...lysosomes did not rupture for approximately 4 hours and in fact did not release the fluorescent dye until after reaching the postmortem necrotic phase of injury. ... The original suicide bag mechanism of cell damage thus is apparently not operative in the systems studied. Lysosomes appear to be relatively stable organelles...."

Messenger RNA and Protein

20 Million Year Survival of DNA

ADDENDUM: A 1997 paper[130] critical of earlier work which attempted to recover DNA from ancient sources said "Whereas ancient DNA sequences from specimens younger than 100 000 years old have now been replicated independently (Hagelberg et al. 1994; Hoss et al. 1994; Taylor 1996), we have singularly failed to recover authentic ancient DNA from amber fossils."

For present purposes the distinction between 100,000 and 100,000,000 years is not critical: both are substantially longer than the time that a person might reasonably expect to stay in cryonic suspension.

Cell Cultures taken after "Death"

Information Loss and Ischemia

As the ischemic interval lengthens, the level of damage increases. It is not clear exactly when information loss begins or when information theoretic death occurs. Present evidence supports but does not prove the hypothesis that information theoretic death does not occur for at least a few hours following the onset of ischemia. Quite possibly many hours of ischemia can be tolerated. Freezing of tissue within that time frame followed by long term storage in liquid nitrogen should provide adequate preservation of structure to allow repair [note 19].

MEMORY

It appears likely that short term memory, which can be disrupted by trauma or a number of other processes, will not be preserved by cryonic suspension. Consolidation of short term memory into long term memory is a process that takes several hours. We will focus attention exclusively on long term memory, for this is far more stable. While the retention of short term memory cannot be excluded (particularly if chemical preservation is used to provide rapid initial fixation), its greater fragility renders this significantly less likely.

To see the Mona Lisa or Niagara Falls changes us, as does seeing a favorite television show or reading a good book. These changes are both figurative and literal, and it is the literal (or neuroscientific) changes that we are interested in: what are the physical alterations that underlie memory?

Briefly, the available evidence supports the idea that memory and personality are stored in identifiable physical changes in the nerve cells, and that alterations in the synapses between nerve cells play a critical role.

Shepherd in "Neurobiology"[38, page 547] said: "The concept that brain functions are mediated by cell assemblies and neuronal circuits has become widely accepted, as will be obvious to the reader of this book, and most neurobiologists believe that plastic changes at synapses are the underlying mechanisms of learning and memory."

Kupfermann in "Principles of Neural Science"[13, page 1005] said: "Because of the enduring nature of memory, it seems reasonable to postulate that in some way the changes must be reflected in long-term alterations of the connections between neurons."

Eric R. Kandel in "Principles of Neural Science" [13, page 1016] said: "Morphological changes seem to be a signature of the long-term process. These changes do not occur with short-term memory (Figure 65-6 [not reproduced here]). Moreover, the structural changes that occur with the long- term process are not restricted to the [sic] growth. Long- term habituation leads to the opposite change---a regression and pruning of synaptic connections. With long-term habituation, where the functional connections between the sensory neurons and motor neurons are inactivated (Figure 65- 2[not reproduced]), the number of terminals per neuron is correspondingly reduced by one-third (Figure 65-6[not reproduced]) and the proportion of terminals with active zones is reduced from 40% to 10%."

Squire in "Memory and Brain"[109, page 10] said: "The most prevalent view has been that the specificity of stored information is determined by the location of synaptic changes in the nervous system and by the pattern of altered neuronal interactions that these changes produce. This idea is largely accepted at the present time, and will be explored further in this and succeeding chapters in the light of current evidence."

Lynch, in "Synapses, Circuits, and the Beginnings of Memory"[34, page 3] said: "The question of which components of the neuron are responsible for storage is vital to attempts to develop generalized hypotheses about how the brain encodes and makes use of memory. Since individual neurons receive and generate thousands of connections and hence participate in what must be a vast array of potential circuits, most theorists have postulated a central role for synaptic modifications in memory storage."

Turner and Greenough said "Two non-mutually exclusive possible mechanisms of brain information storage have remained the leading theories since their introduction by Ramon y Cajal [omitted reference] and Tanzi [omitted reference]. The first hypothesis is that new synapse formation, or selected synapse retention, yields altered brain circuitry which encodes new information. The second is that altered synaptic efficacy brings about similar change."[22].

Greenough and Bailey in "The anatomy of a memory: convergence of results across a diversity of tests"[39] say: "More recently it has become clear that the arrangement of synaptic connections in the mature nervous system can undergo striking changes even during normal functioning. As the diversity of species and plastic processes subjected to morphological scrutiny has increased, convergence upon a set of structurally detectable phenomena has begun to emerge. Although several aspects of synaptic structure appear to change with experience, the most consistent potential substrate for memory storage during behavioral modification is an alteration in the number and/or pattern of synaptic connections."

It seems likely, therefore, that human long term memory is encoded by detectable physical changes in cell structure and in particular in synaptic structure.

Plastic Changes in Model Systems

"Using horseradish peroxidase (HRP) to label the presynaptic terminals (varicosities) of sensory neurons and serial reconstruction to analyze synaptic contacts, we compared the fine structure of identified sensory neuron synapses in control and behaviorally modified animals. Our results indicate that learning can modulate long-term synaptic effectiveness by altering the number, size, and vesical complement of synaptic active zones."

Examination by transmission electron microscopy in vacuum of sections 100 nanometers (several hundred atomic diameters) thick recovers little or no chemical information. Lateral resolution is at best a few nanometers (tens of atomic diameters), and depth information (within the 100 nanometer section) is entirely lost. Specimen preparation included removal and desheathing of the abdominal ganglion which was then bathed in seawater for 30 minutes before impalement and intrasomatic pressure injection of HRP. Two hours later the ganglia were fixed, histochemically processed, and embedded. Following this treatment, Bailey and Chen concluded that "...clear structural changes accompany behavioral modification, and those changes can be detected at the level of identified synapses that are critically involved in learning."

The following observations about this work seem in order. First, several different types of changes were present. This provides redundant evidence of synaptic alteration. Inability to detect one type of change, or obliteration of one specific type of change, would not be sufficient to prevent recovery of the "state" of the synapse. Second, examination by electron microscopy is much cruder than the techniques considered here which literally propose to analyze every molecule in the structure. Further alterations in synaptic chemistry will be detectable when the synapse is examined in more detail at the molecular level. Third, there is no reason to believe that freezing would obliterate the structure beyond recognition.

Implications for Human Memory

It seems likely that knowledge of the morphology and connectivity of nerve cells along with some specific knowledge of the biochemical state of the cells and synapses would be sufficient to determine memory and personality. Perhaps, however, some fundamentally different mechanism is present in humans? Even if this were to prove true, any such system would be sharply constrained by the available evidence. It would have to persist over the lifetime of a human being, and thus would have to be quite stable. It would have to tolerate the natural conditions encountered by humans and the experimental conditions to which primates have been subjected without loss of memory and personality (presuming that the primate brain is similar to the human brain). And finally, it would almost certainly involve changes in tens of thousands of molecules to store each bit of information. Functional studies of human long term memory suggest it has a capacity of only 10^{^9} bits (somewhat over 100 megabytes)[37] (though this did not consider motor memory, e.g., the information storage required when learning to ride a bicycle). Such a low memory capacity suggests that, independent of the specific mechanism, a great many molecules are required to remember each bit. It even suggests that many synapses are used to store each bit (recall there are perhaps 10^{^15} synapses -- which implies some 10^{^6} synapses per bit of information stored in long term memory).

Given that future technology will allow the molecule-by- molecule analysis of the structures that store memory, and given that such structures are large on the molecular scale (involving at least tens of thousands of molecules each) then it appears unlikely that such structures will survive the lifetime of the individual only to be obliterated beyond recognition by freezing. Freezing is unlikely to cause information theoretic death.

TECHNICAL OVERVIEW

The Nature of This Proposal

It is unreasonable to think that the current proposal will in fact form the basis for future repair methods for two reasons:

First, better technologies and approaches are likely to be developed. Necessarily, we must restrict ourselves to methods and techniques that can be analyzed and understood using the currently understood laws of physics and chemistry. Future scientific advances, not anticipated at this time, are likely to result in cheaper, simpler or more reliable methods. Given the history of science and technology to date, the probability of future unanticipated advances is good.

Second, this proposal was selected because of its conceptual simplicity and its obvious power to restore virtually any structure where restoration is in principle feasible. These are unlikely to be design objectives of future systems. Conceptual simplicity is advantageous when the resources available for the design process are limited. Future design capabilities can reasonably be expected to outstrip current capabilities, and the efforts of a large group can reasonably be expected to allow analysis of much more complex proposals than considered here.

Further, future systems will be designed to restore specific individuals suffering from specific types of damage, and can therefore use specific methods that are less general but which are more efficient or less costly for the particular type of damage involved. It is easier for a general-purpose proposal to rely on relatively simple and powerful methods, even if those methods are less efficient.

Why, then, discuss a powerful, general purpose method that is inefficient, fails to take advantage of the specific types of damage involved, and which will almost certainly be superseded by future technology?

The purpose of this paper is not to lay the groundwork for future systems, but to answer a question: will cryonics work? The value of cryonics is clearly and decisively based on technical capabilities that will not be developed for several decades (or longer). If some relatively simple proposal appears likely to work, then the value of cryonics is established. Whether or not that simple proposal is actually used is irrelevant. The fact that it could be used in the improbable case that all other technical progress and all other approaches fail is sufficient to let us decide today whether or not cryonic suspension is of value.

The philosophical issues involved in this type of long range technical forecasting and the methodologies appropriate to this area are addressed by work in "exploratory engineering."[1, 85] The purpose of exploratory engineering is to provide lower bounds on future technical capabilities based on currently understood scientific principles. A successful example is Konstantin Tsiolkovsky's forecast around the turn of the century that multi-staged rockets could go to the moon. His forecast was based on well understood principles of Newtonian mechanics. While it did not predict when such flights would take place, nor who would develop the technology, nor the details of the Saturn V booster, it did predict that the technical capability was feasible and would eventually be developed. In a similar spirit, we will discuss the technical capabilities that should be feasible and what those capabilities should make possible.

Conceptually, the approach that we will follow is simple:

1. Determine the coordinates and orientations of all major molecules, and store this information in a data base.
2. Analyze the information stored in the data base with a computer program which determines what changes in the existing structure should be made to restore it to a healthy and functional state.
3. Take the original molecules and move them, one at a time, back to their correct locations.

An obvious inefficiency of this approach is that it will take apart and then put back together again structures and whole regions that are in fact functional or only slightly damaged. Simply leaving a functional region intact, or using relatively simple special case repair methods for minor damage would be faster and less costly. Despite these obvious drawbacks, the general purpose approach demonstrates the principles involved. As long as the inefficiencies are not so extreme that they make the approach infeasible or uneconomical in the long run, then this simpler approach is easier to evaluate.

Overview of the Brain.

How Many Molecules

We proceed in the same way for the lipids (lipids are most often used to make cell membranes) -- a "typical" lipid might have a molecular weight of 500 amu, which is 100 times less than the molecular weight of a protein. This implies the brain has about 175/500 x 6.02 x 10^{^23} or about 2 x 10^{^23} lipid molecules.

Finally, water has a molecular weight of 18, so there will be about 1400 x 0.8/18 x 6.02 x 10^{^23} or about 4 x 10^{^25} water molecules in the brain. In many cases a substantial percentage of water will have been replaced with cryoprotectant during the process of suspension; glycerol at a concentration of 4 molar or more, for example. Both water and glycerol will be treated in bulk, and so the change from water molecules to glycerol (or other cryoprotectants) should not have a significant impact on the calculations that follow.

These numbers are fundamental. Repair of the brain down to the molecular level will require that we cope with them in some fashion.

How Much Time

The time required for a ribosome to manufacture a protein molecule of 400 amino acids is about 10 seconds[14, page 393], or about 25 milliseconds to add each amino acid. DNA polymerase III can add an additional base to a replicating DNA strand in about 7 milliseconds[14, page 289]. In both cases, synthesis takes place in solution and involves significant delays while the needed components diffuse to the reactive sites. The speed of assembler-directed reactions is likely to prove faster than current biological systems. The arm of an assembler should be capable of making a complete motion and causing a single chemical transformation in about a microsecond [85]. However, we will conservatively base our computations on the speed of synthesis already demonstrated by biological systems, and in particular on the slower speed of protein synthesis.

We must do more than synthesize the required molecules -- we must analyze the existing molecules, possibly repair them, and also move them from their original location to the desired final location. Existing antibodies can identify specific molecular species by selectively binding to them, so identifying individual molecules is feasible in principle. Even assuming that the actual technology employed is different it seems unlikely that such analysis will require substantially longer than the synthesis time involved, so it seems reasonable to multiply the synthesis time by a factor of a few to provide an estimate of time spent per molecule. This should, in principle, allow time for the complete disassembly and reassembly of the selected molecule using methods no faster than those employed in biological systems. While the precise size of this multiplicative factor can reasonably be debated, a factor of 10 should be sufficient. The total time required to simply move a molecule from its original location to its correct final location in the repaired structure should be smaller than the time required to disassemble and reassemble it, so we will assume that the total time required for analysis, repair and movement is 100 seconds per protein molecule.

Temperature of Analysis

Repair or Replace?

Carried to its logical conclusion, we would discard and replace all the molecules in the structure. Having once determined the type, location and orientation of a molecule in the original (frozen) structure, we would simply throw that molecule out without further examination and replace it. This requires only that we be able to identify the location and type of individual molecules. It would not be necessary to determine if the molecule was damaged, nor would it be necessary to correct any damage found. By definition, the replacement molecule would be taken from a stock-pile of structurally correct molecules that had been previously synthesized, in bulk, by the simplest and mos