Chapter VI · THE CONTRIBUTIONS OF BIOLOGY AND PHYSIOLOGY

Weismann’s immortality of the germ plasm and his denial of the inheritance of acquired qualities—The truth and limitations of his views—The theories of Hering and Simon—Metchnikoff’s conception of the disharmonies in man, of the rôle of intestinal flora and their products, of euthanasia, and of the means and effects of prolonging life—C. S. Minot’s conception of the progressive arrest of life from birth on as measured by declining rate of growth and his neglect to consider the dynamic elements—C. M. Child’s studies of rejuvenation in lower and higher forms of life in the light of the problems of senescence—J. Loeb’s studies of the effects of lower temperatures, of toxins, and ferments—The preservation of cells of somatic tissues potentially immortal under artificial conditions—Account of the studies of Carrel, Pozzi, and others—Investigations upon the effects on sex qualities and age of the extracts and transplantations of glands, from Claude Bernard—Investigations of Eugene Steinach on the interchange of sex qualities and rejuvenation by glandular operations in animals and man—G. F. Lydston’s work—Serge Voronoff’s experiments and his exposition of the achievements and hopes of glandular therapy—Some general considerations in view of work in this field.

Next to Darwin, though by a wide interval, August Weismann (d. 1914, a.e. 80) has most influenced general biological thought. His failing eyesight at middle age caused him to abandon the microscope for biological thinking, a field where there was a great need of synthesis and expert theory and in which he developed great power and influence. His hierarchy of metamicroscopic vital units, his dogma of the non-inheritance of acquired qualities in confutation of the prevailing Lamarckianism, and his demonstration of the continuity of the germ plasm have been theses of great interest and centers of very active discussion, even outside the special field of zoölogy, although in the latter doctrine, which chiefly concerns this discussion, he was in a sense anticipated by Owen, Jäger, Nussbaum, and especially by Sir Francis Galton, as he later found.164 He first set forth the now generally accepted view that most of the primitive unicellular organisms do not die and also sought to explain how death first entered the world.165 He says:

We cannot speak of natural death among unicellular animals, for their growth has no termination which is comparable with death. The origin of new individuals is not connected with the death of the old; but increase by division takes place in such a way that the two parts into which an organism separates are exactly equivalent, one to the other, and neither of them is older nor younger than the other. In this way countless numbers of individuals arise, each of which is as old as the species itself, while each possesses the capability of living on indefinitely by means of division.

Each of these one-celled individuals thus lives on and grows, till its surface, through which all nutritive substance is absorbed and which increases at a less rapid rate than its cubic content, becomes relatively too small, so that the creature can no longer be nourished through it and the mature cell faces the alternative either to die or divide into two halves; and, accepting the latter, becomes, by division, two smaller daughter cells that, as the food-absorbing surface becomes now relatively greater, are rejuvenated, although their combined substance is exactly the same as that of the mother cell of which they are simply bifurcations. As, thus, the substance of the parent cells all goes over into the offspring resulting from the fission, nothing is lost in the process, not even an envelope or membrane, as Götte, Weismann’s chief earlier critic, thought was the case in encystment. Thus there is no vestige or rudiment of a corpse. Nothing is sloughed off. It is in this sense that such creatures are immortal. They have gone on growing and dividing thus ever since life began and will continue to do so until it ceases. Thus there is a direct continuity from first to last that is unbroken by anything that can be called death. If once and so long as these single-celled creatures were the only or highest forms of life, death or anything like it was unknown. In all this process, of course, nothing like conjugation, mating, or fertilization occurs.

That this is not mere theory the experiments and observations of many subsequent investigators, especially Woodruff and his pupils, have shown. In thirteen and a half years he found paramecia had divided some 8,500 times, and the process is still going on as actively as at first. Of these results Raymond Pearl166 says, “If in 8,500 generations—a duration of healthy reproductive existence which, if the generations were of the same length as in man, would represent roughly a quarter of a million years in absolute time—natural death has not occurred, we may, with reasonable assurance, conclude that the animal is immortal.” Thus it is that larger, older cells are constantly being regenerated by spontaneous division and natural death does not occur among most protozoa.

They simply grow and divide in an ever alternating rhythm and this was the fundamental cadence in the song of life. If the large or mature stage is, in any sense, a prelude of old age, division in the same way represents rejuvenation. The latter is thus almost, although perhaps not quite, as primordial as the phase of growth itself, and among the most ancient and persistent of all the heritages that higher forms of life received from the lower is this power to grow young. Thus the systole and diastole of the heart of the Zoölogos began. The monad becomes a duad; the individual, a dividual, almost as inevitably as the former grows; and the processional through this tiny life cycle contains in it the promise and potency of countless other processes that developed from it later. Thus even a colony of the far more complex coral polyps may develop perhaps for thousands of years from a single individual.

Now, while protozoa may occasionally conjugate and thus prelude a higher form of reproduction and while the simpler metazoa may propagate by fission or budding, reminiscent of the older way, the general mode of propagation among many-celled organisms follows what seems at first a very different law. In these forms a sperm cell or spermatozoön must penetrate a germ cell or an ovum and then the zygote, or fertilized egg, immediately begins to reorganize itself from within and to divide into two, four, eight cells, etc.; and these divisions produce cells not all exactly like the mother cell but differentiation begins. In some species, as early as the first few divisions certain cells are set apart as germ cells, devoted exclusively to the purpose of reproduction. From these ova and spermatozoa arise. While others, far more in number and aggregate bulk and increasingly so as we ascend the scale of life, become more and more specialized for the production of different organs, structures, and tissues. These gradually lose the power to produce entire individuals. It is these that produce, and their descendants that constitute, all the rest of the body, or soma, and so are called the somatic cells. It is these and their progeny only that die while the germ cells, a very minute portion of the entire body in the higher forms of life, still continue, like the protozoa, to divide and grow in sæcula sæculorum, and it is they that, in a mundane sense, are immortal. Of course very few of the circa four hundred ova produced during the sex life of an average human female and vastly less of the three hundred and forty billions of spermatozoa, according to Lote’s estimate, produced by the average male167 become mature individuals. Most of them perish by the way and all those in the body at its death perish, of course, with it. But sex cells, or rather the germ plasm, even in the highest animals, including man, which attain their goal and produce mature individuals of a new generation, continuing to follow the old formula of eternal growth and division though vastly slower, remain still deathless.

Thus life is a really unbroken continuum from its beginning to its end and we are all connected, as it were, by direct physical participation with the life of our progenitors. Each individual produces a few germ cells that reach the goal of maturity and many somatic cells doomed to death; and in the next generation each repeats the same process. Some flagellate spores, for example, when they divide, lose only the flagellum, which each new individual has to reproduce for itself and this is the rudiment of the corpse that in the higher forms of life becomes indefinitely more bulky and complex; while underneath all this increasing punctuation by death, as it developed, the old plasmal immortality still persists. On the other hand, all forms of fission and agamic budding, so common a method of reproduction in plants and often found in simpler forms of multicellular animal life, such as sponges and coelenterates, are reminiscent of the protozoan fashion.

Thus we see that death came into the world not by reason of sin, as theology teaches, but because of differentiation. As cells acquired the power to produce more and more specialized organs and functions they lost the power to reproduce the entire body and they lost it progressively—almost in exact proportion as their power of multiplication became specific. Thus, as we should expect, we find in the early stages of this differentiation cells that can be influenced toward the old general or the new and more specific powers of reproduction. Yet back of all the fact remains that life itself is essentially perdurable and that we can explain death better than we can explain life. Death is thus not necessary or universal but is derived and is, in a sense, a product of slow development; and we can conceive a stage of evolution in which natural death did not occur at all but was always due to external accidents. Indeed, Weismann goes so far as to say that the difference between the germ and the soma is so great that the latter, with all its fortunes, has little or no influence upon the former; and by his doctrine that acquired traits and qualities are not inheritable he seems to draw a hard and fast line separating the mortal from the immortal parts or organisms. He also devoted the greatest ingenuity in evolving an intricate scheme of biophores, ids, idants, determinants, etc., inherent in germ cells, in order to explain the phenomena of heredity. His studies have had great influence in directing the attention of investigators to the most elementary structures and functions of germ plasm and the remarkable changes within cells that occur in the very earliest stages of embryonic development; while, as we shall see, many of the most recent researches have been directed, since his work was done, to the conditions under which somatic cells in different tissues of the animal body can be made to proliferate and grow, under carefully controlled conditions, more than it was possible for them to do under conditions afforded them while they remained parts of the body in which they were developed.

Here I deem it in point to observe that the adoption in its extreme form of the theory of preformation versus epigenesis, or the assumption that no qualities due to the experiences of the soma can have any influence upon germ plasm or affect heredity, would be to revert to views very like those of the old creationists. From Weismann we may well lay to heart that this influence is very slow and slight in any one or even a large number of generations, suggesting a very long prehistory for the germ plasm of higher organisms. But to hold that nothing in the recent past or the near future of the environment within or without the individual can ever in the least affect innate qualities is to throw ourselves into the arms of a fatalism that more or less blights all the motives of reform and amelioration of conditions or of educational influences in their widest scope. On the contrary, we hold that the ultimate goal of all the improvements of life or mores is to better heredity, that most precious and ancient of all the many forms of values and worths, and that the degree in which they do this is the final criterion of all really worthy endeavor in the world. If the good life of a long series of generations of our ancestors does not in the least tend to make their offspring a little better born and give them some slightly better chance for a worthy, long, and happy life, quite apart from all postnatal, parental, and other influences, the taproot of all motivations for reforming human conditions is cut, and all efforts in this direction become a little falsetto and every generation must start again at the beginning.

Just now we are told that the whole domain of consciousness since civilization began has had little influence upon the deeper and older unconscious elements of human nature but no one among these psychoanalysts has for a moment insisted that it had none. The moral in both cases is simply that we must now make far larger drafts upon the inexhaustible bank of Time and realize that in the one case, body, and in the other, mind, is immeasurably older than we had deemed them to be, that is, that both germ plasm and the unconscious have been very long in the making and come to us charged with potencies innate in the individual but very slowly acquired—in the one case by the ascending orders of animal life from the first and, in the other, by man and his ancestors. We certainly have not yet heard the last word from zoölogy which, while stressing the hereditary factors, for example, and individual longevity, must admit that old age in general is a more or less acquired character. Before we do so, an important correlation, to which I shall advert later, between these investigations and those in the new field of the endocrine glands and the hormones that have such new and marvelous power of speedy and profound influences upon so many parts of and processes that go on in the body, must be made.168

One of the chief traits of old age is the loss of germ plasm with its power of perennially regenerating life and this loss leaves the soma to slow degeneration. As germ substance decreases individuality generally increases, sometimes in the form of gross selfishness. As the body becomes cadaverous or corpse-like and the springs of love begin to dry up at their source, secondary sex qualities fade and the sexes again become more alike, as in childhood, and the extremely senile are but the husk or shadow of their former selves. Tenaciously as life is clung to, it is at the same time felt to be less worth saving either here or hereafter, for whoever heard of senile decrepitude wanting to be continued beyond the grave. All ideals of a future life assume a restoration of maturity if not of youth. Doddering, desiccating senility has always been abhorrent to gods and men and I know of no either imaginative or scientific writer who has even attempted to describe the senium as it would be if prolonged to its extremest conceivable term, when each organ and function slowly ceased “altogether and nothing first”—ever shorter in stature, more shriveled and emaciated in form, hairless, the voice shrunk to a whisper, tottering, tremors, and then inability to work, move, or even eat; abatement of all natural functions, the senses slowly becoming extinct, teeth and the power of mastication gone, everything in a stage of progressive involution, increasing paralysis of all receptive or effector processes, offensive perhaps to the very senses of those about, seemingly forgotten for the time by death itself, which the poor victim perhaps longs for but is unable to command the means of attaining, feeling himself useless and a grievous burden, a just living mummy, torpid, neither really sleeping nor waking; and in the end with every natural function sinking synchronously but so gradually that observers could not be sure whether each slow breath or heart beat was really the last or just when the Great Divide had really been crossed where Sleep embraces its brother, Death. Something like this would be the fate of the soma, after it had been abandoned by the germ plasm, if a really natural death occurred, that is, if, by some of the many disharmonies that pervade the body, some organ or part did not break down before the others were worn out and drag them to its own doom, which is what always really occurs in fact.

If we look at the matter from the more psychological and Lamarckian viewpoint, suggested, for example, by the thesis of Hering, that memory is the most fundamental trait of organized matter, a view elaborated by Simon’s theory of mnemes and engrams, all experience is more or less permanently registered on the most vital of living substances, which is “wax to receive and granite to retain,” nerve and brain being the next best organs of registration only acting more specifically; while the most generic resultants of experience attain their ultimate goal of being recorded in the structure or functions of the germ plasm and thus becoming permanent acquisitions of the species or race. On this view the apex of life is reached at that stage of it when the influence of the soma upon the germ plasm is greatest. This, of course, ceases when the latter takes its departure with loss of the power to propagate. Thus of all the stages of life, old age and its fortunes alone can never affect heredity. Individuals who live on do so only by the momentum given by germinal energies transmitted from their parents, and only the old are completely isolated from the main currents of the life of the race. They have already died racially or to the phylum and only await a second or individual death. Thus if any large number of such individuals lived on for many decades, they would be an encumbrance; and so Nature, always intent on the interests of the species and so indifferent to the individual, has to leave them to their fate. They may still alleviate individual conditions but can contribute nothing to racial memories in the above sense. The species has “forgotten them and they are of it forgot.”

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Elie Metchnikoff (d. 1916, a.e. 71), a bacteriologist and the successor of Pasteur, who approached the problem of old age from a very different angle and collected many interesting data, was led by his experiments and observations to a unique theory.169 He first sets forth the disharmonies in the life of animals and especially of man in a way that seems pessimistic; but both his volumes are subtitled “optimistic studies” because he finds hope at the bottom of the Pandora casket.

Old age, he thinks, is not due to loss of the power of somatic cells to divide or reproduce themselves but is “an infectious chronic disease, whether manifested by degeneration or an enfeebling of the nobler elements and by the excessive activity of macrophags,” the latter being large wandering cells represented by the white blood corpuscles and which he holds to be true phagocytes or scavengers, which, instead of protecting as they were meant to do, are very liable to turn on and destroy the higher elements of the body. They are thus like an army raised and sent out to destroy menacing savages that may turn and attack its own city. Old age and death, then, according to Metchnikoff, are not due, as Blütschli thought, to the exhaustion of some kind of vital ferment that protozoa and germ plasm have pre-eminent power to make; nor to the mere accumulation of waste, which the more always tend to dump upon the less vital elements of the body; nor, as Delboeuf conjectured, to the precipitation of the substance of organs, which always tend to revert to their inorganic bases; nor to Roux’s hypothesis that organs are always competing with each other for the available nutritive material, and that as and when there is not enough to satisfy all, those that have to starve drag down the rest; nor to the failure of the initial momentum given at impregnation; nor to the fact that at the senium the body has passed beyond the reach of the influences of sex and its products; but it is due to a very rank and variegated flora or fauna of noxious microbes, and especially to the toxic products they make, which tend to accumulate in the large intestine, making it thus a very cesspool or latrine of the most manifold infections.

Darwinists have stressed the advantages of the large intestine for convenience and the avoidance of the necessity of leaving frequent spoors by which animals might be tracked by their enemies. But many species are without it or have it only in rudimentary form and in man its removal by surgery results in no very serious impairment. We may add, too, that more recently psychoanalysts have described the anus and rectum and their functions as centers of various erotic activities, especially but by no means exclusively in children. Here the waste products of the digestive processes are dumped, awaiting removal, and it has long been known that their undue accumulation caused not only local troubles but general malaise, anxieties, and nervous and mental tensions. Metchnikoff and his pupils showed that very soon after birth noxious bacteria find their way to the large intestine and flourish thereafter in great profusion, especially in constipation, and that no cathartics can be relied on for permanent relief, salutary as medicine has always and everywhere found them for mitigation of many diverse ailments. It is the microbes that find their chief nidus here that are the principal cause of old age and if an antidote to their lethal action could be found Metchnikoff believes life could be very greatly prolonged. He attempts to show that among not only mammals but also birds, the species that have developed the large intestine are less long-lived than those in which it is rudimentary, so that in animals generally its relative size and individual longevity are inversely as each other. Most of the digestive processes are completed before food reaches this terminal part of the long alimentary canal and very little save water can be absorbed through its walls, so that rectal feeding contributes very little, indeed, to the total nutritive needs of the body. But it is here that death finds its chief armamentaria and establishes a receptacle, factory, or laboratory of poisons. Not only are there many microbes that here feed on food residues and occasionally pierce the intestinal walls themselves, but they produce putrefactive products that are still more lethal. The chief of these are phenol and indol, both very complex and due to the breaking down of albuminoids, the chief element in meat, peas, eggs, etc. Young people may for a long time show no trace of the deleterious effects due to the absorption of these toxins, but the slight wear and tear of the tissues they cause is cumulative. They produce in animals old-age effects in kidneys, arteries, liver, lungs, muscles, testes, ovaries, and even in the brain, for senility is due to the action of these bacterial invaders and not to time or to wearing out.

So vital and rapidly growing are these bacteria that they would soon, under favorable conditions, outbulk the entire body. But while their numbers are kept down by lack of nutriment and other conditions, nature provides no adequate antidote to their activity. This was found by Woolman and was called glycobacterium, or the sugar-maker. It was found first in the dog, and it can be cultivated in the laboratory and introduced into the body. It transforms starch into sugar without affecting the albuminoids and it is not, like sugar, absorbed before it reaches the large intestine. Thus it is not sugar that is the antidote but the lactic acid of its product and this is found in nature in the bacillus of sour milk, a common article of diet among Bulgarians, who seem to be the longest-lived people in Europe. The results of experiments with this product, first upon rats and other animals, Metchnikoff thought remarkably rejuvenating; and as all know, many substances containing lactic acid were for a long time in great favor, although expectations of its effectiveness have by no means been fulfilled. The death of Metchnikoff himself, too, at the age of seventy-one, who had long and diligently used his own panacea, did not help the confidence of his disciples, for we can never forget the old slogan, “Physician, heal thyself.”

In Sanger’s returns to his questionnaire,170 as well as to my own, one often finds people who use some form of this preparation and with what they deem good results and Metchnikoff’s volumes show such a unique combination of humanistic and scientific interests that they have had wide popularity.

The problems, however, with which he deals are so extremely complicated that his work may really be said to have propounded more problems than he solved. He believed he had found and even named specific phagocytes attacking most, but not all, of the main tissues and organs of the body. Cohorts of them encamp about cells, very slowly absorbing their substance and depleting their energies—some attacking muscles; others, heart and arteries, etc.; others consuming the pigment cells of the hair which, however, as Pohl showed, continues to grow as rapidly in old age as in youth, as do the finger nails; others making the bones porous and brittle by removing the lime from them and transferring some of it to the walls of the arteries; some even specializing to attack brain and nerve cells. We must fight fire with fire, and to do this we must not only introduce the sugar-making bacteria but provide them with food in situ in order that they may do their great work of purifying the cradle or breeding ground of noxious bacilli. Some of his disciples are still enthusiastic enough to believe that just as we purified the Panama Zone; as vaccination has almost annihilated smallpox, which once caused about one-tenth of all deaths; as Behring’s antitoxin has greatly abated the scourge of diphtheria; as Wright’s vaccine has lessened death from typhoid; as Ehrlich’s salvarsan treatment has done so much for syphilis, and as he and Wassermann hope may be done for cancer—so we may yet find and learn how to use a specific that, although it will not realize the dreams of those who once sought an elixir of life, will nevertheless contribute to its perhaps indefinitely great prolongation. This Metchnikoff does not hesitate to call “the most important problem of humanity.” His ideal is what he calls orthobiosis, which is “the development of human life so that it passes through a long period of old age in active and vigorous health leading to the final period in which there shall be present a sense of satiety of life and a wish for death.” Mere prolongation of life in the sense of Herbert Spencer is not in itself desirable. When the wish for death comes, he thinks that under certain circumstances suicide would be quite justifiable. Old age, he believes, will not only be greatly prolonged but will become optimistic. Pessimism he finds commonest among young men, while many avowed pessimists have become optimistic in their old age. Young men will not so precipitately attempt to displace the old, as he finds to be too much the case now, but the latter will attain greater power and influence.

The constitution man has inherited from his anthropoid ancestors is far from fitting his present environment. The greatest disharmony of all is the morbid nature and brevity of the period of old age. Man does not round out his prescribed cycle and develop in its final stage an instinct for and love of death, as he should. He is expelled from the school of life at all stages of its curriculum but always before the final or senior year, until the fact that there was such a final grade has been almost forgotten. It was because man felt himself prematurely cut off that he developed all dreams of resurrection and of another life. Had he completed his life here he would never have wanted or dreamed of another. Had the involution that begins usually in the fifth decade or earlier gone on normally, it would have made each stage of the recessional no whit less delightful than those of the processional of youth till, having withdrawn more and more from life and being in the end quite satiated with it, the individual would have rejoiced to see the limitations that separate him from ultimate reality fall away until he merges, body and soul, into the cosmos from which he came. Only the simplest organisms are immortal and as we ascend the scale and develop a more complex soma, the more impossible does any kind of immortality become. Metchnikoff seeks nothing of this sort but would simply increase the number of years and enrich them in the last phase of our existence so that, instead of being the pitiful remnant it now is and instead of having to console itself so pathetically by the puerile and unsubstantial figments that religions and philosophies have given us, man would enter upon the full heritage that nature intended for him. Thus the highest goal of all endeavor is to overcome the present degeneration of senescence, to cultivate physiological old age; and when this ideal is realized, more and more of the complex and intricate affairs of social, industrial, political, and other forms of life will be left to the old men, for these things require not only technical training but, perhaps even more, the wide view, insight, and common sense for which experience with life is the best school.

Metchnikoff was able to discover only two ideal cases of old people in whom his “instinct for death” was well developed. But he believes that as gerontology advances this instinct will not be the exception but the rule and that the very nature of old age as we know it will be radically transformed. At present we know little more of it than the prepubescent child knows of sex or the embryo of its mother’s milk. When the instinct for death is well developed, we shall long for it as we do for sleep when we are fatigued, for old age is The Great Fatigue. Many instincts of the young are reversed and pass over into their ambivalent opposite at a later stage of life; and so the love of life will, in the end, be transformed into the love of death. Both animal and human parents devote their lives to the service of their offspring during the period in which this is necessary; but when the latter are mature, we often find a reversal of this instinct. Perhaps the intense sensitiveness of ova and spermotozoa displayed in the phenomena of chemotaxis and in the marvelous power of regeneration of lost parts among many lower forms of metazoa, and the many phenomena that led Haeckel to call the soul of cells immortal, are lost later as higher, conscious psychic powers develop; and if so, this shows the marvelous transformability of the primitive impulses that dominate simpler forms of life.

Thus Metchnikoff is a humanist as well as a scientist. He sets down faithfully what he saw through the microscope, but not content with that ventures to indulge his speculative instincts and tell the world what he thinks his discoveries mean for the practical conduct of life and of mind—and that, too, in more or less untechnical terms that make his ideas accessible to intelligent laymen. For him, as for Plato, “philosophy is the art of preparing for death.” He even urged that “the instinct for death seems to lie in some potential form deep in the constitution of man,” and it was this he sought to develop. The only basis for all modern forms of belief in immortality roots in a platonic reminiscence of the processes of the deathless germ plasm, and from this the old soma and the, no whit less, old psyche have departed as far as possible. Psychic life, too, has its proximate beginnings in the intense vitality of germ plasm and cells and from these rudiments the adult human consciousness has so far developed that our conscious psyche knows no more of it than it does of the migrations or depredations of the phagocytes within the body. Man is the most pathetic of beings because of the two tides whose ebb and flow constitute his life—evolution and de- or in-volution, anabasis and catabasis. He has failed, on account of the action of the intestinal fauna within him, to achieve any adequate sense of appreciation, still less enjoyment of the refluent currents. Man is thus deprived of the nascent period in which this wooing of death is due to arise and does not reach his true end or final goal. Dreamy illusions about it have always haunted his soul as unsubstantial surrogates. When man now in the making is finished, what we at present call old age will be a sort of superhumanity, a new and higher story, and its completion will spontaneously bring with it new and deeper insights; and he will approach and finally enter Nirvana with the same zest and buoyancy with which he now takes possession of life.

Crude and amateurish as often is Metchnikoff’s philosophy, his courage, candor, and the strength of his convictions are commendable, and the faith he adds to his knowledge is full of hope. From his ideal thinker, Schopenhauer, he caught the flavor of the Vedanta and Upanishads but he did not see how these very ideals also underlay the mystic hermetic philosophy of the medieval alchemists and their royal art, as modern symbolists like Hitchcock and Silberer interpret them; and to this I shall revert later. If he overestimated the value of his panacea and ventured into fields of other experts in which he was ignorant and where he was often mistaken, he has at least made a very valuable addition to the yet all too meager literature on senectitude, which all thoughtful and intelligent aging people can read not only with profit but with pleasure, if only they have escaped from the narrow limits of orthodox Philistia. To have really edified this now ever growing section of all civilized countries is a real culture service. His work is uniquely inspired by a spirit psychologically very akin to that which impelled Buddha when he set out on his mission of finding The Way, stimulated to do so by the sight of an aging man and a putrefying corpse.171

Charles Sedgwick Minot, an embryologist, (d. 1914, a.e. 62) devoted most of his maturer years to a study of the phenomena of growth, keeping and daily weighing many young animals, especially guinea pigs, and he has left us a good compendium of his life work.172 Stated in the most general terms, he held that old age and death were progressive phenomena that began in the individual with life itself, that the best method of measuring vitality was the rate of growth, and that this constantly diminishes and finally ceases. As soon as, for example, guinea pigs recover from the disturbances caused by their birth, which are great and last two or three days because they are born at a very advanced stage of development, they add from 5 per cent to 6 per cent to their weight during a single day. But this percentage diminishes, so that by the end of the first month they add only 2 per cent; at ninety days, only 1 per cent; and the diminution continues, rapidly at first and then more slowly. Calculating the time to make successive additions of 10 per cent, there are twenty-five of these additions; and not until we reach the seventeenth addition do we find nine days or more necessary. The twenty-second addition takes four days, the later ones being somewhat irregular. The first ten per cent increment often comes in two days.

Chicks, too, are born highly developed, and so lose during the first day. Then the daily percentage of increase is greater than in the guinea pig. From the sixth to the tenth day inclusive the average is nearly but not quite 9 per cent; at the end of the third month, only 2 per cent. Rabbits are born very immature and, being less developed, grow more rapidly. The average for males of the first five days of growth is over 17 per cent. The rabbit thirty days old has about the same daily percentage of increase as the new-born guinea pig. The human child takes 180 days to double its weight; a horse, 60; a cow, 47; goat, 19; pig, 18; sheep, 10; cat, 9½; dog, 8; rabbit, 6–7, these rates depending, in part, on the quality of the mother’s milk.

In embryos the rate of growth is still more rapid. The increase in the guinea pig in the first five days is 3,520 per cent, or an average of 704 per cent daily. From the fifteenth to the twentieth day it is 1,058 per cent, or an average of 212 per cent per day. Thus the rate of growth during the foetal period is far more rapid and it is more so in the earlier than in the later stages of embryonic development. The farther back we go, the more rapid is this rate. Thus his curves show a very steep decline in the rate of growth, even in its earlier stages, and this decline continues, although at an ever decreasing rate, to the end. Thus from this point of view the younger creatures are, the more rapidly they are dying. The weight of a fertilized germ he estimates at 0.6 milligram (and he tells us that 50,000 of these could go by mail for a two-cent stamp). Thus the human embryo at birth has increased 5,000,000 per cent of its initial weight. Old age is merely the later result of changes that have gone on at a diminishing rate ever since the ovum from which we originated was fertilized.

Life is growth; the retardation of growth is old age; and its cessation is death. “Senescence is at its maximum in the very young stages, and the rate of senescence diminishes with age” (p. 250). The embryo in its earliest stages rushes toward old age at an almost inconceivable velocity, the new-born infant runs, the child walks rapidly, youth saunters, the adult mopes, and old age only crawls on toward death. In other words, the momentum of life given by impregnation at the age of zero is retarded—most at first and with a diminishing rate at every stage.

Something like this same paradoxical law holds, Minot believed, for the human brain and mind. In one of his Harvey lectures he tells us that the brain of a child at birth is but little differentiated. During the first year it learns all the great adaptations in the physical and human world: time, space, ego, etc. “It learns more during the first year than in all the subsequent years of life” and from birth on the power of learning is rapidly diminished. It declines very fast during infancy, more slowly in childhood, etc.

Accepting Metchnikoff’s dictum that senility is atrophy and that toxins of intestinal origin poison and debilitate tissues so that they succumb to, if they do not actually attract, the predaceous phagocytes (though not proposing his substitute of sour milk for religion and philosophy), Minot points out that we are always throwing off dead cells. Blood corpuscles collapse and are utilized by the liver; the skin is incessantly shedding dead cells, as is the whole intestinal tract and each organ; stature declines some 13 cm.; the brain loses some 19 gms. in weight; the rate and depth of respiration sink; the heart, although growing larger and from the age of prime to senility beating some eight times per minute faster, is nevertheless obstructed in its action by rigidifying arteries; the bones grow spongy and their hard outer part becomes a thin shell; the muscle fibers decline both in size and number, exercise being able to increase only the former and not the latter; both structure and function go on to rigidity and inflexibility after sufficient firmness and size have been attained, till the part becomes too hard and inflexible to function and then is shed as the ripened leaf falls in autumn. But none of these processes are abnormal and hence death is in no sense a disease. Indeed, the power of repair and even recuperation persists far more in the old than has been generally recognized.

The more specific cause of what is generally called old age he finds in the increase of the quantity and the hyperdifferentiation of the structure of the protoplasmic envelope of the nucleus. This protoplasm constitutes the body of the cell. In the earliest stages of cytomorphosis, which follow impregnation, the total amount of nuclear material increases fastest, while later and especially in the senescent cells it is the protoplasm that does so. In the early stages of their embryonic development, too, the cells differ relatively little; but those that constitute the adult body differ so greatly that any skilled observer can tell from which organ they came, whether from the brain, muscle, skin, stomach, liver, etc.; that is, they differentiate more and more as these organs mature. This differentiation is, however, all on the way to death and is never reversible; that is, old body cells never grow young. Nuclei change but it is the protoplasm that changes the most and acquires a new structure, while the composition of the nucleus not only changes less but always retains certain fundamental traits. “The increase of the protoplasm, together with its differentiation, is to be regarded as the explanation (or should we say cause?) of senescence” (p. 134). This is necrobiosis. All old cells, from whatever organ, are thus as recognizable as old faces. “Growth and differentiation of protoplasm are the cause of the loss of the power of growth” (p. 161). He even holds that the first stages of the segmentation of the ovum must be called rejuvenation. On page 167 he says:

The life of the cell has two phases—an early brief one during which the young material is produced and the later and prolonged one in which the process of differentiation goes on; and that which was young, through a prolonged senescence becomes old. I believe these are the alternating phases of life, and that as we define senescence as an increase and differentiation of the protoplasm, so we must define rejuvenation as an increase of the nuclear material. The alternation of phases is due to the alternation in the proportions of nucleus and protoplasm.

In adults, and even in the old, there are always young cells in reserve, often grouped in certain foci, for example, the marrow of the bones, which can in emergencies come forward, take up the function of growth, regenerate lost tissues or, in lower animals, even lost organs. At and even after the death of the aged there are always cells and even parts that are relatively young and growing. There are also, of course, the cells and their matrix, which are very early set apart for the purpose of reproduction, and these, of course, are least of all differentiated. Most cells of the body, however, follow the law of genetic restriction. This means that as differentiation proceeds, the possible directions in which cells can develop become more and more limited till finally they cannot divide at all and lose even the power of nourishing themselves, and so die. The cell and all of it represents life, and Minot has no use for any of the smaller metamicroscopic vital units, gemules, plastidules, plasomes, ideosomes, granules, etc., but thinks that if we wish to accept any kind of ultimate elements of this sort, Weismann’s scheme of them is perhaps, on the whole, the best.

As to the practical questions, how we can help rejuvenation and delay senescence, he states that he has nothing to suggest, although he believes it possible that some time in the future a means may be found of increasing the activities and volume of the nucleus and restricting the growth and differentiation of the protoplasm, which would mean a prolongation of youth.

Minot concludes his volume with a glance at paidology in order to stress the great relative importance for both the bodily and mental development of the early stages of life. The baby develops faster than the child; the child, than the youth, etc., and the rate of psychic unfoldment declines very rapidly from the first, as does that of the body. Week by week, from birth, there is a remarkable expansion of life. Each one of the senses learns how to function effectively and most of them learn to attract the attention, the power of correlating movements and making voluntary ones, and the rudiments of memory and association are laid down, as are the bases of disposition. The infant from the earliest months of its life knows much of the persons and objects in its environment and perhaps has even discovered its own ego. It touches, handles, tastes everything; is an inveterate investigator in an ever widening field of research; has at least a sense of intercourse and companionship; is already at home with time, space, cause, and relation; its feelings, will, and even intellect are developed, and in this order; and the foundations for knowledge and achievement are laid. Thus the child of school age is already senile so far as its infancy is concerned and the boy’s psychic processes are retarded, hard, and unspontaneous. Learning begins to be difficult. Nature no longer shoots the mind up the phyletic ladder but it must climb and grow henceforth by work as well as playwise. Thus man’s mental powers show the same law of progressive retardation as does his physical growth. Instead of drawing the dead line at forty, as Osler did, Minot draws it at twenty-five. Had he been versed in paidology or even known the Freudian conceptions of infancy, he might have greatly amplified his treatment of this stage of the psychic life with which his volume closes. But as it is, there are certain definite criticisms of his conclusions concerning gerontology.

First, as I have said, he only attempts to show the cause and has nothing to say as to the cure of senescence. But he was not in quest of a panacea and was too true to the limitations of his science to pretend to have found one. This will be a disappointment only to those laymen who read him in furtherance of this pragmatic quest.

More serious is the objection that, according to his criterion and curves of declining growth rate, we are really old when we stop growing, for the mature young man and the very old one both are living but a very little above the deadline. On this view, the extinct saurians that grew all their lives were far more vital than creatures that attain a relatively fixed and constant size early and then stop growing. Growth is one measure of vitality, but surely function is another. The dynamic curve of energy and the power of work rises rapidly as that of growth declines and the curve of brain work reaches its apex somewhat later. Determining the increment of pounds or even of foot pounds of energy is not the sole measure of vitality.

Again, if all differentiation is progress toward death, evolution itself, instead of being progressive, is really retrogressive and the ascending orders of life are only a funeral march to the grave. Minot admits this in principle but says that although the advance it brings is bought at the price of death, it is worth all it costs. So it is, but it will not be if the organization and its increase in heterogeneity of structure are only morphological. It pays because of the quest for the good, the beautiful, and the true; because of science, law, love, the control of nature, the organization of society; because of the supreme joy of just being alive and the exhilarating sense of progress. The more evolved all creatures are, including man, the more the pleasure field overlaps the field of pain.

As the hypercivilized mind often longs back, like Rousseau, to an idyllic state of nature; or the world-weary pietist longs back to God; and, we may now add, as the psychoanalyst finds what he deems a psychodynamic equivalent for this trend, in a perhaps yet more exaggerated form, in the flight from reality, seen in dementia præcox and in longing for the mother’s lap and, as Ferenczi says, even for her womb; so Minot’s view of life might almost justify a kind of homesickness for the state of the ovum or the immortal germ plasm, for in this state of incipiency a single-celled organism performs all the functions of life, not only nutritive and reproductive but sensient and motor. It is at this stage, when all cells do all things, that the spirit of life celebrates its highest triumph. The sigh for lost youth is here deepest. Life itself as we know it from this viewpoint seems a little falsetto and pathetic, for it is throughout, in a sense, a fall.

The analyst is also tempted to venture a little farther and to raise the question whether the life of the author of this view itself did not subconsciously contribute a little to reinforce his theory. With a none too rich and full childhood and youth, waiting for years for adequate recognition, passionately if not precociously devoted to the study of embryology, in which field he became one of the ablest and most accomplished of all leaders,173 it would not be surprising if he found certain compensations in devoting his life to a study of that stage in which its manifestations are most active, and ably developed in this field apperception centers he somewhat overworked, while his self-affirmation and the instinctive impulse we all have for due recognition give a subtle self-satisfaction in reiterating the paradox that death is most active near the beginning rather than the end of the life cycle. Whether this suggestion has any validity or not, no one has ever more challengingly presented the problem of why the rate of growth declines from first to last, and whether it be due to an inevitable loss of the initial momentum or biological élan vital or to checks, arrests, and inhibitions of it, some of which may be removed. The very intensity of its early manifestations, if it gives us a haunting sense of loss also reinforces the hope that the high potential with which we all started somehow, sometime, may be better conserved, so that perhaps here, again, as with Metchnikoff’s views, the morale of Minot’s conclusions is, on the whole, optimistic.

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Charles Manning Child, professor of biology in the University of Chicago, has given the most comprehensive statement of his problem to date from the standpoint of his science, although, as we shall see, much has been done since.174 His most interesting and important contribution for our purpose is his refutation of the older view that life is always a progressive process and that true rejuvenescence does not occur. Of course, in higher animals the progressive features are predominant and development ends in death. But the above generalization does not take due account of what occurs in lower organisms, while even in man and other mammals the different tissues do not undergo senescence either alike or synchronously. Some, for example, cells of the epidermis remain relatively young till and after the death of the individual. In other tissues such replacement of old, differentiated, or dead cells by younger ones occurs more or less extensively and tissue regeneration following injury occurs more or less in all tissues save only the nervous system. Such regeneration retards the aging of the tissue or organ as a whole. Minot thought that in such cases regeneration arises from cells or parts of cells that have never undergone differentiation, so that even in such cases development is progressive and not regressive. Even if he is right in maintaining that fibrillar substance cannot regenerate, it must be noted that new fibrillar substance does arise in continuity with the old, while isolated cells apparently do not produce it. Child maintains that there is differentiation in such cases and that these regenerating cells have returned to a kind of activity characteristic of the early stages of embryonic development; that is, that cells can assume an activity characteristic of an earlier stage. “Even in the outgrowth of new nerve fibers from the central stump of a cut nerve there is return to a process of growth and development which is normally characteristic of an earlier stage of development.” Thus regression and differentiation do occur in most tissues of man and higher animals, although cells of one tissue can never produce those of another.

Again, after hibernation regeneration is often extensive. The large proportion of young cells in the body in such cases renders the animal as a whole appreciably younger than at the beginning of hibernation, so that the periodic cycle of activity and hibernation is much like an age cycle. This rejuvenescence may begin during the hibernation, when the animal is living on its own substance. Again, we see periodic changes that resemble the age cycle in glands. In the pancreas cell, for example, the loading of the cell is both morphologically and physiologically similar to senescence, and the discharge, to rejuvenescence. In this case the change occurs in individual cells without cell reproduction. Even the cells of the nervous system throughout mature life possess no appreciable capacity for differentiation and regeneration beyond the power to regenerate fibers arising from them. Child believes that the effect of a change in mental occupation or of a vacation may afford “some slight degree of rejuvenescence of the nerve cells.” Verworn, he tells us, distinguishes between fatigue due to accumulations that check metabolism and exhaustion due to lack of oxygen, both of which may cause senility in nerve cells. “Thus exhaustion resembles senility as death from asphyxiation resembles death from old age.” Recovery from exhaustion is not the same sort of change as rejuvenescence except as it involves increase in the rate of oxidization. But fatigue and recovery constitute a cycle resembling closely the age cycle.

Studies of starvation suggest the same thing. Various experiments have shown that in the later but premortal stage of starvation there is a certain activation of vital processes, including heat production, and it is possible that this has some significance for regeneration. Higher animals are apparently unable to use their own tissues as a source of nutrition to any such extent as the lower forms can do, and this is probably connected with a higher physiological stability of the tissue components. The body weight often does, however, increase and become greater after starvation than it was before, so that a fasting period is followed by an increase in vigor and body weight and hence the wide belief in its therapeutic value. On the other hand, the injurious effects of over-nutrition in man are supposed to be due to the accumulation of food or to intoxication, but it is possible that overnutrition actually increases the rate of senescence by augmenting in the cellular substratum not only the decomposition of food but other substances that decrease the rate of metabolism. There are certainly many instances of longevity in man on a low diet. Again, after certain bacterial diseases, for example, typhoid, the body weight often becomes greater and vigor increases. While low diet often does good, it may, on the other hand, aggravate many diseases. Frogs and salamanders may live a long time without food and undergo great reduction, and starvation sometimes has a directly rejuvenating effect. The animals grow much more rapidly afterward and use a larger percentage of nutrition in growth and attain a larger size than those continuously fed.

Death of cells apparently from old age occurs at every stage of development and many cells do not die when the individual does, for he does so only because some tissue or organ that is essential reaches the point of death. Some have thought glands are primarily responsible for it; but others, whose view Child adopts, hold that it is the nervous system, especially its cephalic part, that dies first in man. In various insects and, for example, the salamander, death occurs almost at once after the exclusion of the sexual products, but this is exhaustion. In most, the length of life of the individual is determined by that of the shortest-lived essential organ or of the tissue that is least capable of regression and rejuvenation and the development of which, therefore, remains most continuously progressive. In cold-blooded animals where the rate of metabolism is dependent on external temperature, senescence can be reduced by cold, and in certain lower invertebrates by the simple method of underfeeding. When cells lose the capacity to divide, they differentiate, grow old, and sooner or later die, although death everywhere is the result of final progressive development if this process goes far enough and is not interrupted by regression caused by the need of repair, reproduction, or lack of food. Death is due, thus, to increased physiological stability of the substratum of the organism or to an increasing degree of differentiation that this general stability makes possible. And as individuation increases, death becomes more and more inevitable. Rubner calculated the total energy requirements in calories for doubling the body weight after birth and the requirements per kilogram in body weight for the whole period of life, for a number of domestic animals. His totals for all, except man, showed close agreement, and hence he concludes that the amounts of energy required are the same in all species except for man, who has a far greater amount of energy, that is, a smaller percentage of the energy of food is consumed in growth and maintenance of body weight and more in activity than in other animals. Very likely domestic animals expend less energy than their wild congeners but it is certainly difficult to correlate these results with Minot’s criteria of age as measured by the decrease of growth.

Child concludes that senescence is more continuous in man than in the lower forms. His long evolution has given a physiological stability to the protoplasmic substratum and a high degree of individuation results from this. But the central nervous system, being least capable of progressive change, always dies first, so that the length of man’s life is that of his nervous system and physiological death and senescence inhere in its fortunes. In the lower forms the death point may never be attained under normal conditions because of the low stability of the substratum and the consequent decrease of individuation that permits the frequent occurrence of a high degree of rejuvenation. But in the higher forms of life the capacity for the latter is limited by greater stability; and this, again, has been acquired through a process of evolution lasting through so many millennia that we must certainly “admit that this task [man’s rejuvenation] may prove to be one of considerable difficulty.”

Thus, according to Child, whose views are the most philosophical and insightful in the field of biology up to date for our purposes, senescence and rejuvenescence are both going on all the time in all cells and organs and are not special processes. In most cells and in most lower organisms dedifferentiation and despecialization of structure and function, which we may term in general regressive tendencies, are always less pronounced than progressive impulsions, while the latter predominate still more in the higher forms of life. It is “quite impossible to account for the course of evolution and particularly for many so-called adaptations in organisms without the inheritance of such acquired characters, but since thousands or ten thousands of generations may be necessary in many cases for inheritance of this kind to become appreciable, it is not strange that experimental evidence upon this point is still conflicting” (p. 463). Germ plasm is not something apart from or uninfluenced by all that goes on in its immediate environment within the body. Regression and dedifferentiation involve reconstitution and always approximate reproduction. To state the matter roughly, all processes involved both in growing old and in growing young might conceivably be arranged on a kind of Porphery ladder with agamic forms of indefinite reproduction, as illustrated in unicellular organisms or in germ plasm at the lower or summum gens end, and the most differentiated cells that have progressively lost the power of reproducing the whole organism, regenerating lost parts, power to grow, divide, and nourish themselves, at the top of the ladder, representing the infima species. On such a ladder, development, differentiation, and individuation is progress up, and all rejuvenating activities are descent toward the most generalized function of perpetual self-reproduction. This conception is in very suggestive harmony with the analogous psychoanalytic law of restitution to mental health by reversion to a more primitive state of psychic development, for all these methods might be called rejuvenation cures.

Physiological integration, with its increasing stability of the structural substratum, makes senescence cumulative as we go up the scale of evolution, so that it is ever less balanced or offset by rejuvenation, reproduction, or other regressive changes, as is the case with simple organisms whose life cycle consists merely of brief alternating phases of progression and regression, for the large protozoan cell about to divide is old compared with the two smaller daughter cells formed from it. Senescence is retardation and rejuvenescence is the acceleration that works by transforming, readapting, and even sloughing off old and useless structures. It will take long to modify the course of evolutionary processes that are the result of millions of years of alternating progressive and regressive changes, but not only the phenomena of rejuvenescence but “sports” and saltatory mutation, to say nothing of the findings of recent experiments showing how life and even activities of somatic cells separated from the body and given a more favorable environment may be indefinitely prolonged, point toward a vast reservoir of vitality. Thus we come to a new appreciation of the incalculable energy behind all the phenomena of animate existence and the hope is irrepressible that somehow, although we have as yet no idea how or when, we may abate or inhibit the forces that check or repress it and man may emerge into a fuller and even a longer life.

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Jacques Loeb, of the Rockefeller Institute, has devoted himself for many years, with a rare combination of great learning and originality, to problems directly or indirectly bearing upon old age and death.175 As his studies of tropism show, he is prone to mechanical and chemical interpretations; and since science has more or less eliminated smallpox, typhoid, yellow fever, malaria, rabies, diphtheria, meningitis, etc., the citizens of scientific nations will sometime, he thinks, be guaranteed a pretty fair probability of a much longer duration of life than they now enjoy. If we define life as the sum of all those forces that resist death, which means disintegration, the latter is comparable to digestion, which transforms meat into soluble products by two ferments, pepsin in the stomach and trypsin in the intestine. These ferments break up the mass into molecules small enough to be absorbed by the blood, and both of them exist not merely in digestive organs but probably in all living cells. They do not destroy our body, perhaps because the coöperation of both is required to do so and this is possible only at a certain degree of acidity, which cannot be reached in the living body because respiration is constantly removing acid. Death thus really comes when respiration ceases.

Of course there is another cause of disintegration, namely, microörganisms from the air and in the intestines. During life the cells are protected by a normal membrane that is destroyed in death and then the action of the microörganisms can superpose itself upon that of digestion. Thus in man death is stopping the breath and this may be done by poison, disease, etc. The problem is whether there is any natural death, for if not we ought to be able to prolong life indefinitely. But we cannot experiment on man because neither the intestines nor respiratory tract can be kept free from microbes. A Russian, Bogdanow, solved this problem for the fly, putting its fresh eggs into bichlorid of mercury, which a few survived, with no microörganisms on the outside. These eggs were then developed on sterilized meat in sterile flasks and Guyemot raised 80 generations of fruit flies thus. Loeb himself and Northrop raised 87 generations. Their dead bodies were transferred to culture media such as are used for the growth of bacteria and more were produced thus for years. Hence fruit flies freed from infection and well fed would not entirely escape death and probably higher organisms would thus die from internal causes were external ones excluded. Eggs, for example, those of starfish, ripen and disintegrate very rapidly if not fertilized by the process of autolysis, which acts only after the egg is ripe. The fertilized egg, however, does not degenerate in the presence of oxygen but dies in its absence, so that we might say that the fertilized egg is a strict aërobe and the unfertilized, an anaërobe. The entrance of the spermatozoön saves the life of the egg.

Is natural death due to the gradual production in the body of harmful toxins or to the gradual destruction of substances required to keep up youthful vigor? If the latter, the natural duration of life would be the time necessary to complete a series of chemical reactions that would produce enough of the toxins to kill. Now, the period necessary to complete a chemical reaction diminishes rapidly when the temperature is raised, and increases when it is lowered. This time is doubled or trebled when the temperature is lowered by 10° C. The influence of temperature on the rate of these processes seems typical. If the duration of life, then, is the time required for the completion of certain chemical reactions in the body, we should expect it to be doubled or trebled when we lower the temperature. We can test this only where, as in our flies, infection is avoided. Northrop put their fresh eggs on sterilized yeast at a temperature of 0.2° C., and the higher temperatures selected were 5°, 10°, and 25°. All the flies died at nearly the same time when kept in the same temperature. The total average duration of life was 2½ days at 30° C., when nearly all of them died. At 10° C. it was 177 days. Thus heat accelerates all chemical action, and here we have the duration of life increased from 200 to 300 per cent. In man the body temperature is constant, for example, 35.5° C. whether in the tropics or the Arctic regions. If we could reduce our temperature, we might live as long as Methuselah. If we could keep the body temperature at 7.5° C. and follow the above ratio, we should live about 27 times 70 or about 1,900 years. Thus the duration of life seems to be the time required for the completion of a chemical reaction or a series of them. The latter may be the gradual accumulation of harmful products or the destruction of substances required for sustaining youth. Not only are unicellular organisms immortal and the life of all their successive generations a continuum, but a bit of cancer tumor can be transplanted to other individuals and there grow larger, and a bit from this second individual transferred to a third, and so on indefinitely; so that the same cancer cell continues to live on in successive transplantations throughout many individual lives. It has thus outlived many times the natural life of the mouse. Indeed, it seems to be able to live on indefinitely and Carrel has shown that this is true of other normal cells. Thus death may not be at all inherent in the individual cell but only be the fate of more complicated organisms in which the different types of structure depend on each other. Certain cells are able to produce substances that slowly become harmful to some vital organ or center and its collapse brings death to the whole.

In man there is no sharp limit between youth and maturity unless it be marked by puberty, but in lower forms of life it is demarcated by a metamorphosis. The tadpole, for example, becomes a frog in the third or fourth month of its life and this process can be accelerated by feeding the creature with thyroid, no matter from what animal. Gudernatsch was able to make frogs no larger than a fly. Allen showed that the tadpole with the thyroid removed can never become a frog, although it may live long and continue to grow larger than the usual tadpole; but if such aged tadpoles are fed with thyroid they promptly become frogs. Salamanders metamorphose by merely throwing off the gills and changing the skin and tail, and the Mexican axoloti maintains the tadpole form through life; but even it, when fed with thyroid, promptly metamorphoses. Schwingle induced metamorphosis in tadpoles by feeding them with a trace of inorganic iodine. Thus the duration of the tadpole stage seems to be the time required to secure a certain compound containing iodine. Insects hatched as maggots will become chrysalides and then flies, but if thyroid is fed to the maggot it accelerates the metamorphosis, although we do not know whether it is due to the accumulation or formation of definite compounds.

Loeb sought to determine whether the duration of the maggot in the larval stage could be due to temperature and he found that this had effects similar to those described above. The larval period lasted 5.8 days at 25° C. and 17.8 days at 15°. The total duration of life was 38.5 days at 25° and 123.96 at 15°, both ratios being 1 to 3. Thus the influence of temperature upon the larval period was like that which it exerted on adult life. The same effect he found in salamanders, all of which suggested to him the conclusion that the duration of life and of the larval period is really the time required for the completion of certain chemical reactions. The cessation of respiration, which means death, and alterations in circulation, which mean metamorphosis or the death of youth, are critical periods and perhaps both points are reached when a certain toxin is formed in sufficient quantity or when a necessary substance is destroyed or reduced. Thus a shortened youth can, in amphibians, be prolonged by modifying the temperature or offering the specific substance that causes metamorphosis, namely, iodine or thyroid. There is no end to the substances capable of hastening death; shall we ever find one that can prolong life?176

Pearl’s experiments on the fruit fly177 show that where long- and short-lived strains are mixed, the first generation they produce is longer-lived than either parent and that for subsequent generations Mendelian laws hold even for longevity, so that there is increased vigor in the hybrid generation due to the mingling of germ plasms that are different. As to bacterial invasion, the stability and resistance of the organism is also a factor, but by rearing insects kept free from all such invasion it appears that “bacteria play but an essentially accidental rôle in determining the length of the span of life in comparison with the influence of heredity.” Pearl criticizes the conclusion of statisticians like Hersch that poverty shortens human life, despite the fact that this is perhaps the most potent single environmental factor affecting civilized man to-day. But we have no real evidence that if the conditions between the rich and poor were reversed the death rate would also be reversed. The influence of high temperature, which is known to accelerate all the metabolic processes, does not interfere with the predominant influence of heredity because it only accelerates life processes exactly in the same way that it accelerates chemical activities and the same is more or less true of the influence of the secretions of the endocrine glands.

Pearl concludes178 that it has already been demonstrated that cells from nearly every part of the metazoan soma are potentially immortal, even in the case of tumors by transplantation, though of course not yet for such exceedingly specialized structures as hair and nails. Under artificial conditions cells from nearly all organs can be made to long outlive the body from which they are taken, just as grafts from apple trees may be passed on indefinitely to successive generations. Thus death is not a necessary inherent consequent of life in even somatic cells but “potential longevity inheres in most of the different kinds of cells for the metazoan body except those which are extremely differentiated for peculiar functions.” The special conditions under which this occurs are often very complex and differ greatly for different tissues and animals, and we shall probably know far more later of the chemico-physical conditions necessary to insure continuous life, for these studies are new, having begun barely twenty years ago. The reason that all these essential tissues are not actually immortal in multicellular animals is that the individual parts do not find in the body the conditions necessary for their continued existence, each part being dependent upon other parts. This view differs from Minot’s that there is a specific inherent lethal process going on within the cells themselves that causes senescence. Pearl concludes “that these visible cytological changes are expressive of effects, not causes, and that they are the effects of the organization of the body as a whole as a system of mutually dependent parts and not a specific inherent and inevitable cellular process. Cells in culture in vitro do not grow old. We see none of the characteristic senescent changes in them.” Thus it may be inferred that when cells show characteristic senescent changes it is because they are “reflecting in their morphology and physiology a consequence of their mutually dependent association in the body as a whole and not any necessary progressive process inherent in themselves. Thus senescence is an attribute of the multicellular body as a whole consequent upon its scheme of morphologic and dynamic organization.” The lethal process, thus, does not originate in the cells themselves. “In short, senescence is not a primary attribute of the physiological economy of cells as such.”

It has long been known, as we have seen, that unicellular organisms could go on dividing indefinitely and that germ plasm had a potential mundane immortality; but no one had suspected that highly organized and differentiated somatic cells, which had lost the power of producing the whole individual and could only produce cells of their own special tissue, had this power. Recent experiments, however, indicate that under certain highly elaborated conditions they, too, can be made to live and even grow indefinitely and that this growth can not only be observed but measured under the microscope. Many attempts had been made by many individuals to grow tissues artificially to see their development, their functions, and decay, in both health and disease. This can now be done by taking pieces of living tissue from the body, for science has never produced a single living cell, and placing it in artificial media made out of blood plasma especially prepared, for nutrition for such a bit of tissue deprived of access to the normal circulation of the blood is the prime condition for such growth.179 Indeed, until Carrel, who had long been interested in the regenerative processes of scars, succeeded in actually causing cells of the connective tissue to grow after being deprived of the circulation of the blood, this was supposed to be impossible. Leo Loeb had already produced artificial growth within and without the body as early as 1907, and in such processes that utilized the body fluid it was found that the same course was followed as in nature, so that the processes in such culture media approximated those that followed grafting. In 1907 Harrison gave details of such a process that seemed convincing, although he worked only on cold-blooded animals, cultivating nerve fibers from the central system of the frog. Carrel extended this method to warm-blooded creatures and mammals, studying especially the laws of regeneration of tissues after surgical wounds.

The method of these remarkable achievements, now often repeated, is to put tiny bits of living tissue in a plasma of blood serum that will coagulate. The blood must be deprived of its cells by the centrifugal process and must generally be taken from the animal for which the tissue is to be cultivated or, at any rate, generally from the same species, although this is not without exceptions, for chicken tissue has been grown in the blood of human beings, dogs, and rabbits; morbid tissue, perhaps, like cancer, being most indifferent. The tissue is taken from an etherized subject, with every possible precaution against bacteria, chilling, or drying, and so liable is it to be killed by exposure to air that it is best dissected in serum. Both plasma and tissue are kept in cold storage and the time during which it can be thus kept varies very greatly with different animals. The bit of tissue must be very small because only the outer edge can get the nourishment when deprived of the normal blood circulation, for when the piece of tissue is large, all but the periphery dies. To see these changes of form, small bits of tissue are grown on the inside of a coverglass of a microscope slide that has been overlain with a prepared plasma, sealed with paraffin and put into an electric incubator provided with a microscope. The period before growth begins varies but when it occurs, the microscope shows the direct division of the nuclei and the growth taking the form either of layers or of radiating chains, depending on whether epithelial or connective tissue is being developed. Each tissue, whether normal or morbid, develops very precisely tissue of its own kind, and sometimes as, for example, with cancerous tissue, the growth is so rapid that it can be observed with the naked eye. This, of course, opens an immense field of observation and experiment, for example, immunity, protection against antibodies, redintegration, regulation of growth of the whole or parts, and perhaps especially rejuvenation and senility, to say nothing of the character and the influence of the secretions from all the glands. The trouble at first was that the artificial growth was so short-lived; but by changing the medium often and by frequent washing away of the waste products in a salt solution, it was found that the life and growth of these isolated bits of tissue could be very greatly prolonged. It seemed that the process of decay was due to the inability of tissues to eliminate waste products. So in 1912 Carrel’s problem was whether these effects could be overcome.

To solve this problem bits of the heart and blood vessels of a chick embryo were grown. These growths were immersed in salt solution for a few minutes and then placed in the new plasma and it was soon found that thus the tissue could be made to live on indefinitely. Growth is more rapid the earlier the stage of it and it soon declines; hence the advantage of using tissue from embryos. But by subjecting these artificial growths to washings it was found that they were many times greater at the end than at the commencement of the month, showing that they do not grow old at all. Thus C. Pozzi says:

The pulsations of a bit of heart which had diminished in number and intensity or ceased could be revived to a normal state by washing and passage through a new solution. In a secondary culture two fragments of heart, separated by a free space, beat strongly and regularly, the larger fragment 92, the smaller 120 times a minute. For three days the number and intensity of pulsations of the two parts varied slightly. On the fourth they diminished considerably in intensity, the large fragment beating 40, the smaller 90 times. When the culture was washed and placed in a new medium, the pulsations again became strong, the larger one 20, the smaller one 60 times a minute. At the same time, the fragments grew rapidly, and in eight hours they were united and formed a mass of which all the parts beat synchronously.

Pozzi again says:

On January 17 the fragment of a chicken heart embryo was placed in plasma. It grew readily on a thick crown of conjunctive cells. In three days the pulsations, which were regular and strong at the beginning, grew feeble and ceased completely, and this state continued for more than a month. On the 29th of February, the culture, which had been subjected to fourteen passages, was dissected and the central film placed in a new medium. After the fifteenth passage it contracted rhythmically, with pulsations as strong and frequent as on January 17, viz., from 120 to 130 per minute. During March and April this fragment of a heart continued to beat from 60 to 120 times per minute. As the growth of the conjunctive tissue became more active, it was necessary, before each passage, to extirpate the new connective tissue formed around the muscle. On April 17 the fragment beat 92 times, agitating all the mass of the tissue and the neighboring parts of the middle of the culture. On May 1 the pulsations were feeble and they were given their thirty-fifth passage. In the manipulation the muscular tissue was stretched and torn so that the contractions ceased.

Thus experiment seems to establish the fact that even connective tissue, composed of not the most highly developed but of vigorous though low-level cells, is immortal. Senility and death result because in normal conditions the blood does not succeed in removing waste products. Could science only wash them away in a living organism, life might be indefinitely prolonged. It is these connective tissues that give support to the textures that compose the body and that chiefly make up bone, cartilage, ligaments, and the lymph network, the cells of which are endowed with special properties of growth and play a great rôle in rejuvenating injured tissue. All this work, in a sense, started from Claude Bernard’s principle that the life of an organism is dependent on the interaction of its cells and the medium in which they grow. Thus, to understand the process by which the body develops and why it must yield to decay and death, we must inquire into the cause of the loss of character of these interactions; and this was impossible until tissue could be grown outside the body so that the processes might thus be brought within the range of the microscope and all its conditions under control. Carrel’s first effort, thus, was directed toward the way in which the medium affected the life of the cell and in constituting this medium of plasma from the blood of dogs and chickens he found that the older the animal from which the blood was taken, the less rapidly and extensively the tissues grew in it. In the blood of a relatively old animal the increase became so slight as to be practically nil. These comparative experiments were made, Grandcourt tells us, with the blood of animals from five months to five years of age, and there was enormously greater activity on the part of the blood of growing animals. Thus it would seem that when an animal attains its size and stops growing, its blood undergoes progressive changes till it lacks, more and more, the dynamic power of youth. So the problem was whether the plasma could be given the force of youth so far as its action on growing cells was concerned and this was accomplished by mixing it with juices extracted from the embryo. Experiments, too, were made with a strain of connective tissue cells that had been kept in artificial life for more than sixteen months. It was divided into two parts, one of which was grown on adult plasma and the other in a mixture of two parts, one of plasma and the other of embryonic juice. In two days the ring of tissue around the second part was three times as great as that around the first. Some of these tissues, passed through a salt solution 130 times, doubled their area in forty-eight hours. Another, washed 57 times, increased in volume fifteen times in ten days, etc. These rapid growths, however, could not be duplicated in normal plasma which was then further modified. Thus the different media have a pretty constant effect upon the rate of growth. Carrel says: “The special rapidity of the growth of the tissue depends so much on the composition of the medium that it may become possible to use as a reagent of the dynamic value of the humors of the organism a strain of cells adjusted to life in utero.” If human connective tissue could be preserved in the condition of permanent life as the connective tissue cells of a chicken are preserved, the value of the plasma of an individual might be approximated by the cultivation in it of a group of these cells and by the observation of the rate of their multiplication. Such observations do suggest some indication of certain values of the blood of an organism and may give us some clue to old age.

Thus in the course of development the activity of the tissue is apt to vary in the body as a whole and in its parts. It therefore became a question whether each particular condition was permanent or whether the dynamics of the cell changes through the action of the medium upon it. To determine this, several bits of tissue, each having its own dynamic power, were cultivated in media exactly alike and differences in the character of the growth were noted. Then the influence of the medium began to tell. Measurements of the changes undergone on the part, in turn of a fast- and slow-growing tissue, showed that the former had lowered its activity one-half in forty-eight hours, while the latter had multiplied its activity by six. This process continued until the level of uniformity was reached, when the conditions of growth remained equal in all cases. Thus it appears that though, in the beginning, certain substances that the tissues had accumulated had the effect of accelerating or retarding its activity in the medium, yet in time the latter overcame these conditions and growth was brought under the laws of its own special mechanism. Thus the sum of the investigations on the influence of the medium on cells is that it may not only change the dynamic possibilities of the tissue but the character of the change may be regulated by a carefully considered modification of the medium (Grandcourt).

All this work involves the theory that the cells make such demands upon the nutrition supplied by the medium that they deplete it and then become indirect means of introducing into the life process a chemically destructive activity (catabolism). The result is a gradual slowing down of cell growth, which is progressive aging and death. A very analogous course was that followed in the earlier artificial cultivations. The tissues lived a short span of days and then died. But the process of degeneration could be obviated by salt solutions and other processes so that tissues now grow in vitro for a year and a half and may continue to multiply faster than those of the embryo. Thus for such tissues senility does not exist and the question naturally arises whether we can ever hope to accomplish anything of this sort inside the body.

Carrel in 1914 reported a strain of connective tissue that had undergone 358 passages and had then reached the twenty-eighth month of its life in vitro. It was detached from the heart of a chick embryo seven days of age, which pulsated for 104 days and gave rise to a large number of connective tissue cells. These multiplied actively for the first two years, a great many cultures having been derived from this strain every week. The fragment of the tissue usually doubled in forty-eight hours, though rapidity of growth was subject to fluctuations. One striking result is seen by comparing the amount of tissue produced by a given culture in forty-eight hours this year with that produced in the same tissue by the same strain of cells a year before. This shows that the activity of the strain had increased, although this might, of course, be due to improvement of technic or possibly to a progressive adaptation to life in vitro. Carrel says: “Thus it is conclusively shown that the proliferating power of the strain has in no wise diminished. During the third year of independent life, the connective tissue shows greater activity than at the beginning of the period and is no longer subject to the influence of time. If we exclude accident, the connective tissue cells, like infusoria, may proliferate indefinitely.” In the latest report at hand one of these cultures had been kept alive and growing thus for seven and a half years.

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The original and indefatigable American-Frenchman, C. E. Brown-Séquard (1817–1894) who in 1878 succeeded Claude Bernard in the chair of experimental medicine in the Collège de France, was one of the first experimental physiologists to study the functions of glands and to realize the importance of their secretions. After investigating the suprarenals in animals as early as 1869 and finding that their removal always caused death, he returned to this subject twenty years later to investigate the testicular fluids which, discharged into the blood, “exalted the power of the nervous system and kept up the vital energies.” He even injected the fluids extracted from the testes of animals into his own system hypodermically, with results that he thought distinctly beneficial to himself and says that he “at the age of seventy recovered the force and energy of youth, with manifestations unknown for a number of years.” He thus believed that he had discovered a new therapeutic agent of great rejuvenating power. Berthelot says, “The subject required delicate manipulation, not only because of the extraordinary precautions required for this kind of investigation but of charlatanism, always ready to possess itself of new curative procedures. He did not protest against the abuses by which his name was used to cover industrial enterprises.” He persisted in his idea, and he, more than anyone else, should be called the founder of opotherapy or treatment by extracts from organs. His name will always have a prominent place in the history of endocrinology or the science that deals with the glands that secrete inwardly, a subject that already has a vast and rapidly growing literature, with an essentially new body of facts and insights and, at its present stage of development, yet far more precious hopes and expectations of great discoveries just ahead.

Some of the many commercial products of testicular juices, so very difficult to prepare in a form that can be preserved, were for many years widely used and the best known of these, Pohl’s spermine preparations, are still more or less in demand. But despite Brown-Séquard’s enthusiastic belief in his age-deferring cure, it lapsed from general attention, partly because the initial expectations were too high, until a very few years ago when the problems it had suggested were approached in a new way by a few investigators whose results have not only a high value in themselves but give promise of yet more important and definite subsequent discoveries—and that despite the conservatism and criticism that all efforts to deal scientifically and fundamentally with human sex problems always encounter.

Professor Eugene Steinach, who founded a laboratory of comparative physiology at Prague and was later made director of the biological institute at Vienna, continued to work there until his institute, for which Roux and others have solicited contributions from men of science, to have it opened again, was closed by the war. He began to publish his epoch-making results in 1910. In spring frogs brought to his laboratory he found 8 per cent impotent and also that testicular injection from normal frogs seemed to restore or intensify the embracement impulse and the strength of the forelegs.180 The effect lasted, however, only a few days. Nevertheless he suggests that in borderline cases it might permanently restore fertility. The same process in castrated frogs showed the same effect, only in much less degree, and the injection of substance from the cerebro-spinal centers of these activities seemed to have a certain but very slight effect upon the sex nature.

When ovaries and testes were transferred in guinea pigs a few days old, he found, in general, that through the influences of the hormones from these glands the character of each sex underwent “slow but radical transformation over toward the other.”181 In the one case the male organ atrophied and the breasts were developed, with a disposition to nurse, the hair became finer, the method of growth was transformed into that of the other sex; and the converse occurred when the transplantation was in the reverse direction. The change was thus both morphological and functional and Steinach believes that there is a distinct antagonism of the sex hormones due to transplantation of a heterological gland and that this is not due to biochemical differences of blood but to a distinct antagonism between male and female hormones, which have a sex specificity that is the main factor in directing growth. He distinguishes between the specific sex influence and the antagonism that brings about heterological sex signs, which favor the development of other pubertal glands and control growth, even to the dimensions of the skeleton, both stimulating and inhibiting it. The transplantation can be so effected that the glands of both sexes, in a sense, inhibit each other, so that something like experimental hermaphroditism can be caused. These changes last sometimes through life and occasionally there may be periodic milk secretions in males. Each element checks and may throw the other out of function.

In a later article182 Steinach published results of experiments upon the exchange of sex glands in other animals between the different sexes and found that the female masculated by being given the testes of her brother followed more or less his development rather than her own, almost equaling him in growth, weight, and robustness. This Steinach calls hyper-masculinization and a degree of this follows the development of the glands after transplantation, which the microscope showed was attended by real intussusception. He also showed hyper-feminization, so that we have a change of the ovaries into hypertrophic but analogous pubertal glands, with corresponding change of traits, dependent upon the degree of success or completeness of the operation. Thus he thinks, too, we can explain somatic and psychic precocity by the hypertrophy of these glands. In another article183 the author emphasizes the great variability in the development of sex, both as to size of organs and their functions in different individuals and believes that besides environment, heredity, race, etc., climate has a great deal to do with it. He finds that in warm countries the advent of sex maturity is somewhat earlier in all its aspects, although there is some suggestion that these accelerations may be connected with the development of other secondary traits. Experiments made with animals in artificial climates point to the same result and changes in this direction are observed in animals accustomed to cold that are transported to warm climates.