284
The central theme of this book has been the indefinite improbability of mankind and of men, through eugenic and euthenic techniques. The crucial issue of credibility hinges on the scientific research to date, on which our projections depend. To supplement the previous discussion, we now offer the educated layman and beginning student some selected information of a slightly more detailed and technical nature. (The word "layman" refers to everyone-including almost all physicians and scientists-whose specialty is outside these fields; an "educated layman" is one who is familiar with the language of high school biology.)
Let me warn against over diffidence on the part of the layman, who is apt to deprecate his ability to understand, let alone his competence to judge. While certain details and activities in a scientific discipline can be very difficult indeed, it is also true that intelligent and self confident laymen can often quickly learn enough to participate in some policy decisions in a responsible manner; this happens every day, for example, in the Congress, which despite the jokes turns in some very impressive performances.
It may be worth a slight digression to point out that not
285
only understanding, but even discovery and invention, may occasionally be within the scope of the amateur or beginner, if he is alert, perceptive and bold. (Not many people are. Very few college freshmen can even tell you whether the moon rises in the east or west, even though (a) they have seen it many times, and (b) they have enough information to infer it.) One of the most striking examples I know of invention deferred concerns the hot air balloon, which could have been built by anyone in a cloth weaving society if he noticed that hot air rises; for thousands of years no one made the connection.
Cryobiology
People of our generation are not likely to become supermen unless they survive until a later era. The only promising technique for such survival involves cold storage of either live or legally "dead" patients. In this section we summarize some of the most pertinent research in low temperature biology.
Reaction rates and temperature.
It is well known that many types of reaction are slowed by cooling, typically by a factor of 2 for every 10 degrees Centigrade reduction. This exponential dependence implies that at liquid nitrogen temperature, 196 C, compared to body temperature, 37 C, reactions are slowed by a factor of roughly 8,000,000; at liquid helium temperature, just a few degrees above absolute zero, the factor would be about 2,000,000,000 (51).
Not all reactions behave exactly this way, and there are even some reactions that proceed faster (at least for a while, and in a certain relatively high temperature range) in ice than in liquid water. But many gross observations have verified the general effect; e.g., mammoths frozen for 30,000 years in the Arctic have retained much of their integrity. (137)
286
Instances of freeze-thaw survival.
Even the most extreme cold is not necessarily fatal to living tissue. Human conjunctival tissue and human sperm have survived freezing at less than 1 deg Kelvin (about 459 F)." A great many types of cell suspensions and tissues have survived freezing at liquid nitrogen temperature, and subsequent rewarming. (157)
Some types of cell, and most organs, require special care to survive freezing, storage at cryogenic temperatures and thawing. With such special techniques, usually including a cryoprotective agent to perfuse the tissues, there has been notable (although limited) success in freezing such complex mammalian organs as the dog kidney" and the cat brain (166).
3. Freeze-Store-Thaw damage. There are many modes of freezing damage, not all of them well understood. The mode the layman thinks of first-mechanical stabbing or crushing by ice crystals-is not important in most cases, although in very fast freezing, where crystals form inside the cells, there may be such damage to organelles, membranes and other cellular infrastructure. (107)
The primary mode of damage, at moderate freezing rates, is thought to be chemical (119). As the freezing proceeds, nearly pure water is drawn from the cells and crystallizes in the intercellular spaces as ice, leaving the intracellular medium hypertonic and otherwise unbalanced. Thus the cell is poisoned, and some of its proteins denatured. Prof. Armand M. Karow, Jr. and Dr. Watts R. Webb have developed a theory in terms of the biophysics of bound water lattices (89).
Some deleterious changes may also occur in storage, even at cryogenic temperatures. If the temperature is above 130 C, the recrystallization point for ice, there may be a slow migration of molecules from small ice crystals to the larger ones, because there is an appreciable difference in the vapor pressure, depending on crystal size (144).
Thawing damage may be as important as freezing damage, or more important (157). In many cases of freeze-store-thaw experiments, it is not certain how much of the damage is attributable to which phase. Nonuniform thawing is obviously dangerous, since the life processes are resumed at different times and rates in different parts of the specimen. In some cases a very slow thaw seems to overcome this problem (166). More often, a fast thaw is attempted, sometimes with microwave diathermy or induction beating, but this can produce irregular results, even to the extent of local boiling, which is bad for the health (105).
When sizable organs are frozen and thawed, there may be apparent 100% survival of the cells, yet failure of the organ as a whole. This is often attributed to relatively minor failures in the resuscitation technique; e.g., certain small blood vessels may fail to open again completely, leading to ischemia of parts of the organ and gradual death (144). But it must also be remembered that 100% survival of cells is not always essential; sometimes there is marked damage, yet the organ survives and gradually heals itself to recover fully, Thus, in at least one of the dog kidney experiments, in spite of noticeable damage, there was longterm survival of the kidneys and of the dogs (63)..
4. Cryoprotective agents.
Many substances have been found to have a marked cryoprotective or cryophylactic action, beginning with Rostand's report of the effect of glycerine in protecting frog sperm against freezing damage (147). Glycerine is still one of the most versatile and effective, but may be second to DMSO (dimetbylsulfoxide), which has the additional virtue of great penetrating or diffusing power, as reported notably
288
by Dr. Stanley W. Jacob and others. Another widely used agent is PVP, polyvinylpyrrolidone; still others include ethylene glycol and propylene glycol' and a variety of alcohols and sugars, as well as magnesium salts (37). Their action is not well understood, but may include the prevention of freezing of small amounts of bound water necessary for membrane integrity in the cells (89).
Recently Dr. Peter Gouras has suggested using much higher concentrations of DMSO than customary-perhaps as much as 65%, the eutectic proportion, for which the freezing point is much lower, which raises the possibility of low temperature storage in the liquid phase (59).
5. Other alternatives.
Several workers are investigating the possibility of using very high pressures, in order (a) to prevent ice formation while the temperature is relatively high, and (b) to allow nearly instantaneous thawing. Results so far are inconclusive.
Although low temperature storage is by far the most promising method of longterm preservation, there are others which just barely might work out. One is hibernation (77) Another is freeze-drying, which just conceivably might be applicable to large organisms; and still another is the use of antimetabolites or enzyme inhibitors.
To conclude, we note once more that while present methods of freezing are imperfect, the damage is sufficiently limited to warrant optimism about the eventual revival and repair of people frozen today, or at the very least, to make pessimism untenable.
Gerontology
To imagine that a "normal" life span can be satisfactory in any valid sense is almost certainly a delusion. Any proper
superman will have to have greatly extended life, perhaps indefinitely extended.
A sharply limited life span has been so nearly universal in nature, and its acceptance so psychologically and sociologically necessary, that its inevitability has not been much questioned until recently, despite an occasional Gilgamesh, hsien, Condorcet, or Ponce de Leon. Among all the meta-zoons, only the sea-anemone is agreed to have an indefinite life span, and this lowly creature is more of a loose cell colony than a true metazoon (97). (A very few species of fish and reptile, of a kind which never entirely stop growing, provide questionable cases with inconclusive data.) Among men, the increased life expectancy that civilization brings is almost entirely owing to reduction of infant mortality and infectious disease; in the last two hundred years the life expectancy of an American male after age 60 has scarcely changed (8).
Nevertheless, many students of aging now agree that we shall learn not only to understand senile degeneration, but to prevent and even reverse it; some claim that, to a limited degree, we can do so already. Bernard Strehler: "It appears to me that there is no inherent contradiction, no inherent property of cells or of metazoa, which precludes their organization into perpetually functioning and self replenishing individuals." (163). F. M. Sinex: "The present development of biochemistry and biology suggests the question, 'Why do we get old?' may be answered in the foreseeable future ... preventative therapy is a possibility." (156). Johan Bjorksten: ". . when the age problem itself has been solved, the age dependent diseases headed by cancer and circulatory diseases will automatically fall in line. The full benefit of all other medical research will only be realized when the process of aging can be braked." (14). I. N. Kugelmass: "(Man) may well become master of his own life and lifespan. (97) Seymour Bakerman: "The main objective in the study of
290
aging is to obtain information that can be applied to humans for the prolongation of lifespan and, at the same time, for the maintenance of vitality. (8)
Some experimental and clinical results.
There have been some definite successes in increasing the life span of laboratory animals, and some apparent successes in improving the vitality of elderly human patients. We shall mention a few.
One type of therapy, effective with rats and mice, involves restriction of diet. In 1932 Clive McCay published results of experiments in which life spans of rats were increased about 50% by limiting caloric intake to slow down maturation; the rats remained healthy in most respects, and completed maturation when the diet was normalized. The deprived rats lived up to 1465 days, against a normal span of the control group of up to 969 days. These, and somewhat similar experiments, have been repeated by others; mice have had lifespan doubled by deprivation of a certain amino acid, tryptophan. (14) It is not at all clear whether a restricted diet in childhood would benefit humans.
Many clinical trials with human patients have involved hormone therapy of various kinds. Voronoff's early attempts to graft ape testicles to men had very little success, if any, despite his enthusiasm. (172) Gynecologist Robert A. Wilson, however, has claimed in recent years that hormone therapy has done wonders for some of his women patients, preventing most of the symptoms of menopause and producing, for example, ". . . supple breast contours, taut, smooth, skin, firm muscle tone ... vigor and grace." In fact, he says some of them look, feel and act 20 years younger."' Many human glandular systems have been the subject of study and trial, with varying and unclear success.
The use of cellular therapy has been clouded by sensational stories, but seems to have a core of merit. (Cellular
291
therapy involves injecting patients with foreign cells, typically intramuscular injection of the cells of young or embryonic animals.) The best known clinical practitioner is the Swiss Dr. Paul Niehans, who is rumored to have treated celebrities including W. Somerset Maugbam and Pope Pius XII. Unfortunately, all the people named in the rumors have either continued to age or have died, and the clinical practice has not crossed the Atlantic to the U.S. Nevertheless, serious gerontologists here are impressed by some of the work. In one series of 471 patients, 53% showed long-lasting improvement in hardening of the arteries. (86)
Dr. Benjamin Frank, a New York physician, has a partly worked out theory of nucleic acid therapy for reversal of aging, and has applied it in clinical practice. He has been criticized for lack of well controlled and quantitative experimental design, but says that patients have shown obvious and substantial benefit in remission of symptoms of aging-smoothing of wrinkles, improvement of skin tone, better heart function, and general increase in strength and vigor (54). He also says that two dogs, nearly dead of old age and greatly debilitated at ages 14 and 16 respectively, after being given his treatment improved markedly and lived to 20 and 23 respectively, dying of accident and infectious disease.
Denham Harman, a physician and chemist at the Universities of California and Nebraska, like many others, was impressed by the similarity of radiation damage to senile degeneration, and consequently tried antiradiation drugs to combat senility; he believed he succeeded, in one series of experiments, in extending the lives of mice by 25%. The theoretical basis supposedly concerns the deleterious action of "free radicals"-active, short-lived molecular fragments-produced by radiation (68). Other workers, however, think radiation damage cannot account for more than a small fraction of senile debility."'
I
Some theories.
Gerontology today is to some extent a matter of therapy without theory and theory without therapy. We shall now sketch a few of the theoretical views, without trying to make them systematic or mutually exclusive.
One of the oldest and most general theories is that of depletion of irreplaceable structures. (8) Contrary to popular notions, it is not true that our bodily material is all regularly replaced; it is untrue for many types of cells, including neurons, and it is untrue for some types of molecule within the cells, such as certain molecules in collagen. Loss of such elements may represent deterioration which is ordinarily irreversible. Of course the question remains why, and how the loss occurs, and how it can be prevented or repaired. Understanding of development, of ontogeny, might provide the answers, and this understanding is increasing.
More or less inverse to the depletion theory is another general kind of theory, that of accumulation of harmful elements. Some workers have noted apparent accumulation of "clinkers" of metabolism, inert residues interfering with normal physiology (8). Strehler speaks of possible accumulation of a layer of varnish over various intracellular structures and says they may be related to unsaturated fats which, therefore, contrary to recent advertising, and despite the cholesterol danger, may be more harmful than saturated fats in the diet (163). Still another example of this kind is the "calciphylaxis" theory of Hans Selye, which attributes a substantial portion of aging damage to calcium deposits or reactions (152).
3. Genetic theories of aging are of several kinds. (Obviously, any aging process whatever is related to heredity in a broad sense.) One such general theory is that of genetic instability, the genes being somehow progressively damaged so they transmit erroneous information, fouling up the metabolism. Postulated causes of this instability are of
292
many kinds, and one of the best known is that of somatic mutation, the idea that mutations occur in body cells through radiation (8). But the radiation damage theory, as mentioned, has been pretty well ruled out as a major factor by the work of Muller and others.
4. Another genetic theory is that of gene pleiotropy: a gene which is valuable in terms of the survival of the species during development may eventually have deleterious effects during maturity (156). A variation of this is the idea that genetic design is just imperfect in the sense that it does not take into account certain slow processes or changes in structural protein or lipid, for example. A somewhat similar but more brutal idea is that aging is directly programmed, that evolutionary forces created planned obsolescence because that somehow benefits the race, despite the cost to the individual.
5. Another slightly different view distinguishes organismic aging from cellular aging. In the former there may be disproportionate growth or imperfect repair-a lack of adequate coordination among the control processes of the body, resulting in cumulative insult and eventual death. In cellular death (occurring in cells which do not divide, or which do not divide rapidly or accurately enough) the basic cause or causes might be the same, on a small scale, as those mentioned above and below.
6. R. L. Walford and others have worked on an autoimmunity theory of aging; as age progresses, certain molecules may form or change in such a way that the body no longer recognizes them as " self", and the body is attacked by its own immunologic defenses (173).
7. Finally we have the cross linkage theory, associated with the names of Johan Bjorksten, Sinex, Bakerman and others. This is compatible with several of the aforementioned theories, and suggests that the main cause of aging is the cross-linking of certain large molecules, perhaps
294
especially in collagen. This cross linking more or less glues the molecules together at certain points, reducing their mobility and changing their properties in unacceptable ways (14).
While aging may have several or many causes, the cross-linkage theory seems to be gaining favor, and this is hopeful, because cross-linkage suggests the possibility of relatively easy cure. Dr. Bjorksten believes there must be enzymes in the soil capable of breaking down the cross-linked aggregates-otherwise there would be much more fossil protein in soil. If we can isolate suitable enzymes, they might represent very nearly a "youth serum". (It would not matter if they also broke down noncrosslinked molecules, since normal anabolic processes would take care of replacement of normal molecules removed, if dosage is carefully controlled.)
Genetic Engineering & Euthenics
Superman will be built in several ways: by manipulation of germ plasm before conception, which is genetic engineering in the most straightforward sense; by control of development, in both pre and postnatal phases, to improve the phenotype, which is "euthenics" as narrowly defined; and by a variety of radical interventions to modify the individual, including the use of surgery, pharmacology, symbiotic organisms and many types of prosthetic appliances and auxiliary devices. Let us look at a few of the signposts and preliminary successes.
Despite differences of opinion, there is no lack of bold, optimistic and authoritative predictions on the manipulation of human biology. Nobel laureate Joshua Lederberg has written, ". . . we should learn bow to manipulate chromosome ploidy, homozygosis, gametic selection, full diagnosis of heterozygotes, to accomplish in one or two gen -
295
erations of eugenic practice what would now take ten or one hundred. . . . The ultimate application of molecular biology would be the direct control of nucleotide sequences in human chromosomes, coupled with recognition, selection and integration of the desired genes ... it would be incredible if we did not soon have the basis of developmental engineering technique to regulate, for example, the size of the human brain by prenatal or early postnatal intervention ... When euthenics has worked itself out, we should have a catalogue of biochemically well defined parameters for responses now describable only in vague functional terms. Then we shall more confidently design genotypically programmed reactions, in place of evolutionary pressures and search for further innovations." (100)
Another Nobel laureate, Arthur Kornberg-who has succeeded in synthesizing viruses-mentions a particular possible early application:
(Dr. Stanfield) Rogers has shown that the Shope papilloma virus, which is not pathogenic in man, is capable of inducing production of the enzyme arginase in rabbits ... (and) in the blood of laboratory investigators working with the virus there is a significant reduction of the amino acid arginine, which is destroyed by arginase. This is apparently an expression of enhanced arginase activity. Might it not be possible, then, to use similar nonpathogenic viruses to carry into man pieces of DNA capable of replacing or repairing defective genes?" (96)
The above was published in 1968; in September of 1970 the newspapers reported clinical application of this idea. Twin girls in Germany suffered mental retardation and partial paralysis because of an excess of arginine, due to lack of arginase, owing to hereditary defect, an absence of the gene that normally directs the manufacture of arginase in the body. They were deliberately given a harmless form of the Shope virus in an attempt to change their heredity-
296
possibly the first such attempt in humans. As of this writing, results are not yet known. (Even if successful in this instance, of course, the effect would probably not be to reverse brain damage already incurred, but only to prevent further damage.)
Still another Nobel laureate, James Watson-the codiscoverer of the doublehelical structure of the DNA molecule-speaks of manipulation by "hybridization" of unlike DNA molecules:
If a heated DNA solution is slowly cooled, a single strand can often meet its complementary strand and form a regular double helical molecule. This ability to renature DNA molecules permits us to show that artificial hybrid DNA molecules can be formed by slowly cooling mixtures of denatured DNA from two different species. For example, hybrid molecules can be formed containing one strand from a man and one from a mouse. (174)
This does not mean that we are going to grow mousy men, or manly mice, necessarily, but it indicates a possible way of patching in changes as desired.
The quotation from Watson, above, was published in 1965; in 1970 the newspapers have reported success in mix ing genetic material from four mice-instead of the usual two, male and female-to produce real, live mice. A mouse with four parents! This is already achievement, not speculation, if the reports are accurate.
Eventually-as we have already noted, but not expressed in quite this way-we ourselves will have no parents; i.e., our heredity will be so thoroughly revised and improved that we will no longer, in any important biological sense, be any kin to our historical parents. Or rather, the kinship between ourselves and our historical parents-if they also survive to become supermen-will be fraternal instead of parental; they will share our new, improved characteristics,
297
and none of us will have much in common with our former selves, except memory.
While major genetic engineering for humans is probably not in the immediate future, remarkable new powers of bodily control apparently are. Exceptional people have always shown ability to influence their bodies in ways beyond the "normal". In sporadic, spontaneous cases, there have been such manifestations as the well known "stigmata of the cross", where religious hysterics ooze blood from the hands and feet. In more systematic cases, yogis and hypnotists have been able to induce trances, anaesthesia and changes in metabolic rates. Similar powers are now being studied by somewhat different techniques, including BFT--Bio Feedback Training or "electronic Yoga". Using rather simple conditioning procedures, normal subjects have been taught to control their own heartbeat, blood pressure, and even brain waves, by such investigators as Joseph Kamiya at the University of California and Barbara Brown at the V. A. Hospital in Sepulveda, California (88). It appears that, by a slightly different route, we may soon realize the long deferred promise of hypnosis and selfhypnosis, possibly even to the extent, for example, of selfcontrol of ovulation by women-the ultimate in birth control.
Intermediate between the relative simplicity of BFT and the great difficulty of full genetic engineering, there will be the broad spectrum of techniques including artificial body parts and brain extenders, electronic and chemical stimulation of the brain, ectogenesis or extrauterine gestation, and partial control of development. We shall not go into detail here; one of the best recent lay surveys is Albert Rosenfeld's The Second Genesis (145).
Repair of Damaged Neurons
Many of the foregoing considerations have been sum-
298
marized and extrapolated by Jerome B. White as applied to a special area of great concern to our generation: the repair, especially in the brain, of frozen and resuscitated patients, who may have been considerably deteriorated at death and further damaged by crude freezing methods. The abstract of his paper follows:
An organic cell is a selfrepairing automaton, but if environmental interference exceeds a certain limit, damage will become total. Freezing can be used to halt progressive damage along with all metabolism, but means are required to restore or augment the cellular genetic control program, or enrich the environment to enhance repair ability. It has been proposed that appropriate genetic information be introduced by means of artificially constructed virus particles into a congenitally defective cell for remedy; similar means may be used for the more general case of repair. Progress has been made in many relevant areas. The repair program must use means such as protein synthesis and metabolic pathways to diagnose and repair any damage. Applied to brain neurons, this might destroy long term information content, which appears to be stored in molecular form, often suggested to be in a feedback cycle involving mRNA and protein. This information can be preserved by specifying that the repair program incorporate appropriate RNA tapes into itself upon entry and release them on termination of repair (180).