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Popular Science Monthly/Volume 71/August 1907/The Problem of Age, Growth and Death II

THE

POPULAR SCIENCE

MONTHLY

 

AUGUST, 1907




THE PROBLEM OF AGE, GROWTH AND DEATH
By CHARLES SEDGWICK MINOT, LL.D., D.Sc.

JAMES STILLMAN PROFESSOR OF COMPARATIVE ANATOMY IN THE HARVARD MEDICAL SCHOOL

II. Cytomorphosis. The Cellular Changes of Age

Ladies and Gentlemen: I endeavored in my last lecture to picture to you, so far as words could suffice to make a picture, something of the anatomical condition of old age in man, and to indicate to you further that the study merely of those anatomical conditions is not enough to enable us to understand the problem we are tackling, but that we must in addition extend the scope of our inquiry so that it will include animals and plants, for since in all of these living beings the change from youth to old age goes on. it follows that we can hardly expect an adequate scientific solution of the problem of old age unless we base it on broad foundations. By such breadth we shall make our conclusion secure, and we shall know that our explanation is not of the character of those explanations which I indicated to you in the last lecture, which are so-called 'medical,' and are applicable only to man, but rather will have in our minds the character of a safe, sound and trustworthy biological conclusion. The problem of age is indeed a biological problem in its broadest sense, and we can not study, as we now know, the problem of age without including in it also the consideration of the problems of growth and the problems of death. I hope to so entice you along in the consideration of the facts, which I have to present, as to lead you gently but perceptibly to the conclusion that we can with the microscope now recognize in the living parts of the body some of those characteristics which result in old age. Old age has for its foundation a condition which we can actually make visible to the human eye. As a step towards this conclusion, I desire to show you this evening something in regard to the microscopic structure of the human body.

We now know that the bodies of all animals and plants are constituted of minute units so small that they can not be distinguished by the naked eye, although they can be readily demonstrated by the microscope. These units have long been known to naturalists by the name of cells. The discovery of the cellular constitution of living

PSM V71 D104 Cells from the mouth of the salamander to show mitosis.png

Fig. 3. Cells from the Mouth (Oral Epithelium) of the Salamander, to show the phases of cell division or mitosis.

bodies marks one of the great epochs in science, and every teacher who has had occasion to deal in his lectures with the history of the biological sciences finds it necessary to dwell upon this great discovery. It was first shown to be true of plants, and shortly after likewise of animals. The date of the latter discovery was 1839. We owe it to Theodor Schwann, whose name will therefore ever be honored by all investigators of vital phenomena. What the atom is to the chemist, the cell is to the naturalist. Every cell consists of two essential parts. There is an inner central kernel which is known by the technical name of nucleus, and a covering mass of living material which is termed the protoplasm and constitutes the body of the cell. I will now call for the first of our lantern slides to be thrown upon the screen. It presents to you pictures of the cells as they are found lining the mouth of the European salamander. The two figures at the top illustrate very clearly the elements of the cell. The protoplasm forms a mass, offering in this view no very distinctive characteristics, and therefore offering a somewhat marked contrast with the nucleus which presents in its interior a number of granules and threads. Every nucleus consists of a membrane by which it is separated from the protoplasm, and three internal constituents: First, a network of living material, more or less intermingled with which is a second special substance, chromatin, which owes its name to the very marked affinity which it displays for the various artificial coloring matters which are employed, in microscopical research. The third of the internal nuclear constituents we may call the sap. the fluid material which fills out the meshes of the network. Later on we shall have occasion to study somewhat more carefully the principal variations which nuclei of different kinds may present to us, and we shall learn from such study that we may derive some further insight into the rapidity of development and the nature of the changes which result in old age. While the picture is upon the screen, I wish to call your attention to the other figures which illustrate the process of cell multiplication. As you regard them you will notice in the succession of illustrations that the nucleus has greatly changed its appearance. The substance of the nucleus has gathered into separate granules, each of which is termed a chromosome. These chromosomes are very conspicuous under the microscope, because they absorb artificial stains of many sorts with great avidity and stand out therefore conspicuously colored in our microscopic preparations. They are much more conspicuous than is the substance of the resting nucleus. And this fact, that we can readily distinguish the dividing from the resting nucleus under the microscope, we shall take advantage of later on, for it offers us a means oi investigating the rate of growth in various parts of the body. I should like, therefore, to emphasize the fact at the present time sufficiently to be sure that it will remain in your minds until the later lecture in which we shall make practical use of our acquaintance with it. It is unnecessary for our purposes to enter into a detailed description of the complicated processes of cell division. But let me point out to you that the end result is that where we have one cell we get as the result of division—two; but the two divided cells are smaller than the mother cell and have smaller nuclei. They will, however, presently grow up and attain the size of their parent.

Every cell is a unit both anatomically and physiologically. It has a certain individuality of its own. In many cases cells are found to be isolated or separated completely from one another. But, on the other hand, we also find numerous instances in which the living substance of one cell is directly continuous with that of another. When the cells are thus related, we speak of the union of cells as syncytium. Of this I offer you an illustration in the second picture upon the screen which represents the embryonic connective tissue of man. In this you can see the prolongations of the protoplasm of a single cell body uniting with the similar prolongations from other cell bodies, the cells themselves thus forming, as it were, a continuous network with broad meshes between the connecting threads of protoplasm. The spaces or meshes are, however, not entirely vacant, but contain fine lines which correspond to the existence of fibrils, which are characteristic of connective tissue and at the stage of development represented in this picture, are beginning to appear. It is fibrils of this sort which we find as the main elements in the constitution of sinews and tendons, as, for instance, the tendon of Achilles, at the heel. In a very young body we find there are but few fibrils; in the adult body an immense number.

There is, in fact, as you probably all know, a constant growth of cells; and this growth implies also, naturally, their multiplication. There has been in each of us an immense number of successive cell

 

PSM V71 D106 Example of syncytium.png

Fig. 4. Example of a Syncytium. Embryonic connective tissue from the umbilical cord of a human embryo of about three months, magnified about 400 diameters, c, c, cells; f, inter, cellular fibrils.

 

generations, and at the present time a multiplication of cells is going on in every one of ns. It never entirely ceases as long as life continues. The development of the body, however, does not consist only of the growth and multiplication of cells, but also involves changes in the very nature of the cells, alterations in their structure. Cells in us are of many different sorts, but in early stages of development they are of few sorts. Moreover, in the early stages we find the cells all more or less alike. They do not differ from one another. Hence comes the technical term of differentiation, to designate the modifications which cells undergo with advancing age. At first cells are alike; in older individuals the cells have become of different sorts, they have been differentiated into various classes. This whole phenomenon of cell

PSM V71 D107 Transverse sections of a rabbit embryo.png

Fig. 5. Three Transverse Sections through a Rabbit embryo of seven and one half Days, from series 622 of the Harvard Embryological Collection. A, section 247 across the anterior part of the germinal area. B. section 260 across the middle region of the germinal area. C, section 381, through the posterior part of the germinal area. Magnified 300 diameters.

change is comprehensively designated by the single word, cytomorphosis, which is derived from two Greek words meaning cell and form, respectively. A correct understanding of the conception cytomorphosis is an indispensable preliminary to any comprehension of the phenomena of development of animal or plant structure. I shall endeavor, therefore, now to give you some insight into the phenomena of cytomorphosis as regarded by the scientific biologist. The first cells which are produced are those which form the young embryo. We speak of them, therefore, as embryonic cells, or cells of the embryonic type. Our next picture illustrates the actual character of such cells as seen with the microscope, for it represents a series of sections through the body of a rabbit embryo, the development of which has lasted only seven and one half days. You will notice at once the simplicity of the structure. There are not yet present any of those parts which we can properly designate as organs. The cells have been produced by their own multiplication and are not yet so numerous but that they could be readily actually counted. They are spread out in somewhat definite layers or sheets, but beyond that they show no definite arrangement which is likely to attract your attention. That which I wish you particularly to observe is that in every part of each of these sections the cells appear very much alike. The nuclei are all similar in character, and for each of them there is more or less protoplasm; but the protoplasm in all parts of these young PSM V71 D108 Transverse section of a human embryo spinal cord.pngFig. 6. Portion of a Transverse Section of the Spinal Cord of A Human Embryo of Four Millimeters. Harvard Embryological Collection, series 714. The spinal cord at this stage is a tubular structure. The figure shows a portion of the wall of the tube: the lefthand boundary of the figure corresponds to the inner surface of the tube. rabbits is found to be very similar; and indeed if we should pick out one of these cells and place it by itself under the microscope, it would be impossible to tell what part of the rabbit embryo it had been taken from, so much do all the cells of all the parts resemble one another. We learn from this picture that the embryonic cells are all very much alike, simple in character, have relatively large nuclei, and only a moderate amount of protoplasm for each nucleus to complete the cell.

Very different is the condition of affairs which we find when we turn to the microscopic examination of the adult. Did time permit it would be possible to study a succession of stages and show you that the condition which we are about to study as existing actually in the adult is the result of a gradual progress and that in successive stages of the individual we can find successive stages of cell change; but it will suffice for our immediate purpose to consider the results of differentiation as they are shown to us by the study of the cells of the adult. I will have thrown upon the screen for you a succession of pictures illustrating various adult structures. The first is, however, a section of the embryonic spinal cord in which you can see that much of the simple character of the embryonic cells is still kept. All parts of the spinal cord, as the picture shows, are very much alike, and the nuclei of the cells composing the spinal cord at this stage are all essentially similar in appearance. What a contrast this forms with our next picture, which shows us an isolated so-called motor nerve cell from the adult spinal cord. It owes its name motor to the fact that it produces a nerve fiber by which motor impulses are conveyed from the spinal cord to the muscles of the body. PSM V71 D109 A single isolated motor nerve cell of an ox spinal cord.pngFig. 7. Copy of the Original Figure from the Memoir of Deiters, in which the proof of the origin of the nerve fibers directly from the nerve cells was first published. The memoir is one of the classics of anatomy. It was issued posthumously, for the author died young to the great loss of science. The figure represents a single isolated motor nerve cell from the spinal cord of an ox. The single unbranched axon Ax, is readily distinguished from the multiple branching dendrites. The cell has numerous elongated branching processes stretching out in various directions, but all leading back towards the central body in which the nucleus situated. These are the processes which serve to carry in the nervous impulses from the periphery towards the center of the cell, impulses which in large part, if not exclusively, are gathered up from other nerve cells which act on the motor element. At one point there runs out a single process of a different character. It is the true nerve fiber, and forms the axis, as it was formerly termed; or axon, as it is at present more usually named, of the nerve fiber as we encounter it in an ordinary nerve. This single threadlike prolongation of the nerve cell is likewise constituted by the living protoplasm and serves to carry the impulses away from the cell body and transmit them ultimately to the muscle fibers which are to be stimulated to contraction. In the embryonic

PSM V71 D110 Stained purkinje cell from a human cerebellum.png

Fig. 8 A Large Cell from the Small Brain (Cerebellum) of a Man. It is usually called a Purkinje's cell. It was stained black throughout by what is known as the Golgi silver method, hence shows nothing of its internal structure. After von Kölliker.

spinal cord none of these processes existed, and the amount of the protoplasm in the nerve cell was very much smaller. As development progressed, not only did the protoplasm body grow, but the processes gradually grew out. Some of them branched so as to better receive and collect the impulses; one of them remained single and very much elongated, and acquired a somewhat different structure in order to serve to carry the nervous impulses away. The third picture[1] shows us a section through the spinal cord of an adult fish. It has been treated by a special stain in order to show how certain elements of the spinal cord acquire a modification of their organization by which they are adapted to serve as supports for the nervous elements proper. They play in the microscopic structure the same supporting role which the skeleton performs in the gross anatomy of the body as a whole. They do not take an active part in the nervous functions proper. None of the appearances which this figure offers for our consideration can be recognized in any similar preparation of the embryonic cord. Obviously, then, from the embryonic to the adult state in the spinal cord there occurs a great differentiation. That which was alike in all its parts has been so changed that we can readily see that it consists of many different parts. A striking illustration of this is afforded by the next picture, which represents one of the large nerve cells which occur in the small brain, or cerebellum, that portion of the central nervous system which the physiologists have demonstrated to be particularly concerned in the regulation and coordination of movements. These large cells occur only in this portion of the

PSM V71 D111 Various human nerve cells.png

Fig. 9 Various Kinds of Human Nerve Cells, as described in the Text. After Sobotta.

brain, and, as you see, differ greatly in appearance from the motor cells of the type which we were considering a few moments ago. And, again, another picture illustrates yet other peculiarities of the adult nerve cells. The upper figures in this plate are taken from cells which have been colored uniformly of a very dark hue, in consequence of which

PSM V71 D112 Sections of four sorts of epithelium.png

Fig. 10. Sections of Four Sorts of Epithelium. After Sobotta.

they are rendered so opaque that the nucleus which they really contain is hidden from our view. But the deep artificial color makes it easy to follow out the form of the cells and the ramifications of their long processes. In the middle figures we have cells which have been stained by another method which brings out very clearly to the eye the fact that in the protoplasm of the cell there are scattered spots of substance of a special sort. No such spots can be demonstrated in the elements of the young embryonic nerve cells. To some fanciful observers the spots, thus microscopically demonstrable in the nerve cells, recall the spots which appear on the skin of leopards, and hence they have bestowed upon these minute particles the term tigroid substance. The bottom figures represent the kind of nerve cells which occur upon the roots of the spinal nerves. It is unnecessary to dwell upon their appearance, as the mere inspection of the figures shows at once that they differ very much indeed from the other nerve cells we have considered. We pass now to another group of structures, the tissues which are known by the technical name of epithelia. You can notice immediately in the figures from the skin that the appearances are very different from those we have encountered in contemplating the cells of the nervous system. And you can readily satisfy yourselves by the comparison with the various figures now before you, of the fact that these epithelia are unlike one another. The figures represent epithelium, respectively, first from the human ureter; second, from the respiratory division of the human nose; third, from the human ductus epididymidis, and fourth, from the pigment layer of the retina of the cat. We turn now to a representation of a section of one of the orbital glands. This is very instructive because we see not only that the cells which compose the gland have acquired a special character of their own, but also that they are not uniform in their appearances. This lack of uniformity is due chiefly to the fact that the cells change their appearance according to their functional state. We can actually see in these cells under the microscope the material imbedded in their protoplasmic

PSM V71 D113 Orbital glands prior to and after prolonged secretion.png

Fig. 11. To show the Orbital Glands, A. with the material to form the secretion accumulated within the cells. B. after loss of the material through prolonged secretion. From R. Heidenhain after Lavdowsky.

bodies out of which the secretion, which is to be poured forth by the cells, is to be manufactured. So long as that material for the secretion is contained in the cells, the cells appear large, and their protoplasmic bodies do not readily absorb certain of the staining matters, which the microscopist is likely to apply to them. When, however, the accumulated raw material has been changed into the secretion and discharged from the gland, the cell is correspondingly reduced in bulk, and as you see in this figure, it then takes up the stain with considerable avidity, as does also the nucleus which has likewise become reduced in size. These facts are very instructive for us, since they prove conclusively that with the microscope we can see at least part of the peculiarities in cells which are correlated with their functions. We can actually observe that the cells of the salivary glands are able to produce their peculiar secretion because they contain a kind of substance which in the embryonic cell does not appear at all. There is a visible differentiation of these salivary cells from the simple stage of the embryonic cells. Something similar to this can be recognized in the next of our pictures representing a section of the gland properly known as the pancreas, but which is sometimes termed the abdominal salivary gland for the reason that it somewhat resembles the true salivary. In the cells of the pancreas also we can see the material, which is to produce the secretion, accumulated in the inner portion of the cell, and when it is so accumulated the cell appears enlarged in size and the nucleus is driven back towards the outer end of the cell where some unaltered protoplasm is also accumulated. When this raw material is turned

PSM V71 D114 Pancreatic gland of a dog prior to and after prolonged secretion.png

Fig. 12. Two Sections of the Pancreatic Gland of a Dog. A, the cells are enlarged by the accumulation of material to form the secretion. B, the cells are shrunk because there has been prolonged secretion and part of their substance is lost. From R. Heidenhain.

over into secretion by a chemical change, it is discharged from the cell, the cell loses in volume and in its shrunken state presents a very different appearance, as is shown at B in the figure. It is necessary for the cells to again elaborate the material for secretion before they can a second time become functionally active. Here we have something of the secret of the production of the various juices in the body revealed to us. Other excellent examples of the differentiated condition of the cells are afforded us by the examination of hairs, of which I will show you two pictures. The first represents a section through the human

PSM V71 D115 Cross section of human skin displaying hair follicles.png

Fig. 13. Section of the Human Skin, made so that the Hairs are cut Lengthwise.

skin taken in such a way that the hairs are themselves cut lengthwise and you can see not only that each hair consists of various parts, but also that the cells in these parts are unlike. The follicles within the skin in which the hair is lodged likewise have walls with cells of various sorts. It may interest you also to point out in the figure the little muscle which runs from each hair to the overlying skin, so disposed that when the muscle contracts the "particular hair will stand up on end." Still more clearly does the variety of cells which actually exists in a hair show in the following picture, which represents a cross-section of a hair, and its follicle, but more highly magnified than were the hairs in the previous figure. The adult body consists of numerous organs. These are joined together and kept in place by intervening

PSM V71 D116 Cross section of the root of a hair.png

Fig. 14. Cross section of the Root of a Hair.

substance. The organs themselves consist of many separate parts which are also joined by a substance which keeps them in place. This substance has received the appropriate name of connective tissue. We find in the adult that it consists of a considerable number of structures. There are cells and fibers of more than one kind, which have been produced by the cells themselves. There is more or less substance secreted by the cell which helps to give consistency to the tissue. In some cases this substance which is secreted by the cells becomes tougher and acquires a new chemical character. Such is the case, for instance, with cartilage. Or, again, you may see a still greater chemical metamorphosis going on in the material secreted by the cells in the case of bone, where the substance is made tougher and stronger by the deposit of calcareous material. Nothing like cartilage, nothing like bone, exists in the early state of the embryo. They represent something different and new. The next of our illustrations shows us a muscle fiber of the sort which serves for our voluntary motions, which is connected typically with some part of the skeleton. These muscle fibers are elongated structures. Each fiber contains a contractile substance different from protoplasm, and which exists in the form of delicate fibrils which PSM V71 D117 Muscle fiber of the human tongue.pngFig 15. Part of a Muscle Fiber of the Human Tongue to show the Cross Striations. Two nuclei are included, one of which is shown at the edge of the fiber, the other in surface view. In the adult striated muscle fibers of mammals the nuclei are superficially placed. run lengthwise in the muscle fibers, and is so disposed, further, that a series of fine lines are produced across the fiber itself, each line corresponding with a special sort of material different from the original protoplasm. These cross lines give to the voluntary muscle fibers a very characteristic appearance, in consequence of which they are commonly designated in scientific treatises by the term striated. A striated muscle fiber is that which is under the control of our will. It should perhaps be mentioned that the muscle fibers of the heart are also striated, though they differ very much in other respects from the true voluntary muscles. And last of all for this series of demonstrations, I have chosen a representation of the retina. One can see at the top of the figure the peculiar cylindrical and developing projections, which are characteristic of a retina, projections which are of especial interest because they represent the apparatus by which the rays of light are transformed into an actual sensory perception. After this has been accomplished, the perception is transmitted into the interior substance of the retina, and by the complication of the figure you may judge a little of the complication of the arrangements by which the transmission through this sensory organ is achieved, until the perception is given off to a nerve fiber and carried to the brain. There is not time to analyze all I might present to you of our present knowledge concerning the structure of the retina. But it will, I think, suffice for purposes of illustration to call your attention to the complicated appearance of the section as a whole and to assure you that nothing of the sort exists in the early stage of the embryo. To recapitulate, then, what we have learned from the consideration of these pictures, we may say that in place of uniformity we now have diversity. It should be added, to make the story complete, that the establishment of this diversity has been gradually brought about, and that that which

PSM V71 D118 Section of the human retina.png

Fig. 16. Section of a Human Retina, from Stöhr's Histology, sixth American edition. Although the retina is very thin it comprises no less than twelve distinct layers; the outermost layer is highly vascular. The pigment layer prevents the escape of light. The rods and cones convert the light waves into a sensory impulse, which is transmitted through the remaining layers of the retina to the optic nerve. The total structure is extremely complicated.

we call development is in reality nothing more than the making of diversity out of uniformity. It is a process of differentiation. Differentiation is indeed the fundamental phenomenon of life; it is the central problem of all biological research, and if we understood fully the nature of differentiation and the cause of it, we should have probably got far along towards the solution of the final problem of the nature of life itself.

The size of animals deserves a few moments of our time, for it is intimately connected with our problem of growth and differentiation. Cells do not differ greatly from one another in size. The range of their dimensions is very limited. This is particularly true of the cells of any given individual animal, decent careful investigations have been made upon the relation of the size of cells to the size of animals, and it has been found that animals are not larger, one than another, because their cells are larger, but because they have more of them. This statement must be understood with certain necessary reservations. There are some kinds of animals, like the star-fish, which have very small cells; others, like frogs and toads, which have large cells; so that a star-fish of the same bulk as a given frog would contain a great many more cells. Our statement is true of allied animals. For example, a large frog differs from a small frog, or a large dog from a small dog by the number of the cells. An important exception to this law is offered for our consideration by the cells of the central nervous system, the nerve cells properly so called. This is demonstrated by the slide now before us, which shows us corresponding motor nerve cells of twelve different animals arranged in the order of their size—the elephant, the cow, the horse, man, the pig, the dog, the baboon, the cat, the rabbit, the rat, the mouse, and a small bat. You recognize immediately

PSM V71 D119 Motor nerve cells of various mammals.png

Fig. 17. Motor Nerve Cells of Various Mammals, all from the cervical region of the spinal cord. The cells are represented, all uniformly magnified. After Irving Hardesty.

that there is a proportion between the size of these cells and the size of the respective species of animals. To a minor degree, but much less markedly, there is a difference in the caliber and length of the muscle fibers. But with these exceptions our statement is very nearly exactly true, that the difference in size of animals does not involve a difference in the size of their cells. For the purpose of the study of development, which we are to make in these lectures, this uniformity in the size of cells is a great advantage, and enables us to speak in general terms in regard to the growth of cells, and renders it superfluous to stop and discuss for each part of the body the size of the cells which compose it, or to seek to establish different principles for different animals because their cells are not alike in size.

Now we pass to a totally different aspect of cell development, that which is concerned with the degeneration of cells. For we find that,

PSM V71 D120 Changes in the nerve cells due to aging.png

Fig. 18. Changes in the Nerve Cells with Age.

after the differentiation has been accomplished, there is a tendency to carry the change yet further and to make it so great that it goes beyond perfection of structure, so far that the deterioration of the cell comes as a consequence. Such cases of differentiation we speak of as a degeneration, and it may occur in a very great number of ways. Very frequently it comes about that the alteration in the structure of the cell goes so far in adapting it to a special function that it is unable to maintain itself in good physiological condition, and failing to keep up its own nourishment it undergoes a gradual shrinkage which we call atrophy. A very good illustration of this, and a most important one, is offered us by the changes which go on in the nerve cells in extreme old age. This is beautifully illustrated by the two pictures which are now before us, copied from investigations of Professor Hodge, of Clark University. The two figures represent human nerve cells taken from the root of a spinal nerve. The left-hand figure shows these cells as they exist in their full maturity; the right-hand figure, as they appear in a person of extreme old age. In the latter you will readily notice that the cells have shrunk and no longer fill the spaces allotted to them, the nuclei have become small, and the protoplasm has changed its appearance very strikingly because there have been deposited in it granules of the pigment which impart to these cells an appearance very different from that which they had in their maturity when their functional powers were at their maximum. You will notice also in other parts of the right-hand figure that the atrophy of the cells has led on to their disintegration, that they are breaking down, being destroyed, and that the result of their breaking down will ultimately be their disappearance. Thus the atrophy of a cell may lead to its death. The other two figures[2] upon the screen show us the brain of the humble bee. On the left is the brain of the bee in the condition in which we find it when the bee first emerges from the pupa or chrysalis. The cells are then in a fine physiological condition, but in a few weeks at most the bee becomes old and in the space which belongs to each cell we find only its shrunken and atrophied remnants, the nucleus greatly reduced in volume, and an irregular mass of protoplasm shrunk together around it. These cells have likewise undergone an atrophy and are on their way to death. In other cases we find that there is a change going on which we call necrobiosis, which means that the cells continue to live, but change their chemical organization so that their substance passes from a living to a dead state. No more perfect illustration of this sort of change can be found than that which is afforded by the skin. In the deep layer of the outer skin are the living and growing parts, which we all know from experience are sensitive. As these multiply some of them move up towards the surface; and they are continually shoved nearer and nearer the surface by the growth of the cells underneath. They finally become exposed at the surface by the loss of the superficial cells which preceded them. During this migration the protoplasm of each cell, which was alive, is changed chemically into a new substance which we call keratin, or in common language, horny substance. Ultimately the cell protoplasm becomes nothing but horny substance and is absolutely dead. Here life and death play together and go hand in hand. Hence the term necrobiosis, life and death in one. Another form of degeneration which occurs in many cases is of great interest because it seems as if the cells were making a last great effort; and their final performance is one of enlargement. They become greater in size than before; but there will follow a disintegration of these cells also; and they break down and are lost. This form of degeneration is termed hypertrophic, and represents a third type, as I have stated. In all parts of the body degenerative changes are going on, and they represent collectively a third phase in the cytomorphic cycle. But there is yet one more phase, which is needed to complete the story. That is the phase of the death and final removal of the cells. The degenerative change always results in the death of the cell. In many cases the dead material is removed merely by being cast off, as is the case with the skin. All the scales which peal off from the outer surface of our body represent little scraps or clusters of cells which are entirely dead; and in the interior of the body, in the intestinal canal, and in the glands of the stomach, we find cells continually dying, dropping off from their place upon the walls, and being cast away. Or if we examine the saliva which comes from the mouth, we detect that that also is full of cells which have died and fallen off from their connection with the body and are thus removed. An even more important method of the removal of cells is by a chemical process in consequence of which the cells are dissolved and disappear before our eyes, very much as marble may disappear from sight under the corrosive action of an acid. Indeed, we know that all the parts of the body, so far as they are alive, produce within themselves a ferment which has a tendency to destroy the living substance itself. The production of these destructive agents is going on at all times, apparently, in all parts of the body, which are alive. A striking illustration of this is offered in the stomach. The digestive juice which is produced in the stomach is capable of attacking and destroying living substance, and any organic material suitable for food which is placed in the stomach will, as we know, be attacked by the gastric juices, dissolved to a certain extent by them, and so destroyed. Why then does the gastric juice not attack the stomach itself? This is but one phase of the problem why the body does not continually destroy itself. It has lately been ascertained by some ingenious physiological investigations that the body not only produces the destructive agents, but also antagonists thereto, anti-compounds which tend to prevent the activity of the destroying factors. The whole problem is one of great interest and importance which calls for very much further investigation before we can l)e said to have arrived at a clear understanding of it. But it helps us much in our conception of cytomorphosis to know that all portions of the body are endowed with this faculty of destroying themselves, for it enables us to understand how it is possible that after the degeneration of a cell it will be dissolved away. It is merely that the agents of solution which are ordinarily held at bay are no longer restrained, and they at once do their work. There is another, but comparatively rare, mode of cell-destruction. The cells break up into separate fragments, which are then dissolved by chemical means and disappear, by the method of histolysis above described, or else are devoured by the cells, to which reference was made in the first lecture, and which are known by the name of phagocytes, and to which Metchnikoff has attributed so great an importance. It is unquestionable that phagocytes do eat up fragments of cells and of tissues. and may even attack whole cells. But to me it seems probable that their rôle is entirely secondary. They do not cause the death of cells, but they feed presumably only upon cells which are already dead or at least dying. Their activity is to be regarded, so far as the problem of the death of cells is concerned, not as indicating the cause of death, but as a phenomenon for the display of which the death of the cell offers an opportunity. The subject of the death and disintegration of cells is an exceedingly complex one, and might well occupy our attention for a long time. But it is not permissible to depart from the strict theme which we have before us, and I will content myself, therefore, with throwing upon the screen two tables[3] which illustrate to us the variations in the death of cells and in their modes of removal which are

known at the present time. These tables are taken from a lecture which I delivered in New York a few years ago, which was subsequently published. If any of you should care to make a closer acquaintance with them they are therefore readily accessible to you. How then, from the standpoint of cytomorphosis ought we to look upon old age? Cytomorphosis, the succession of cellular changes which goes on in the body, is always progressive. It begins with the earliest development, continues through youth, is still perpetually occurring at maturity and in old age. The rôle of the last stage of cytomorphosis, that is, of death in life, is very important, and its importance has only lately become clear to us. I doubt very much if the conception is at all familiar to the members of this audience. Nevertheless the constant death of cells is one of the essential factors of development, and much of the progress which our bodies have made during the years we have lived, has been conditional upon the death of cells. As we have seen, cytomorphosis, when it goes through to the end, involves not only the differentiation but the degeneration and death of the parts. There are many illustrations of this which I might cite to you as examples of the great importance of the destruction of parts. Thus there is in the embryo before any spinal column is formed an actual structure which is termed the notochord. In the young mammalian embryo this structure is clearly present and plays an important part, but in the adult it has entirely disappeared, and its disappearance begins very early during embryonic life. There are numerous blood vessels which we find to occur in the embryo, both those which carry the blood away from the heart and those which bring blood to the heart, which during the progress of development are entirely destroyed, and disappear forever. Knowledge of these is to the practical anatomist and surgeon often of great importance. Vast numbers of the smaller blood vessels which we know commonly by the name of capillaries, exist only for a time and are then destroyed. There is in the young frog, while he is in the tadpole stage, a kidney-like organ, which on account of its position is called the head-kidney, but it exists only during the young stage of the tadpole. There is later produced another kidney which, from its position, is called the middle kidney, and which is the only renal organ found in the adult, for the head kidney entirely disappears in these animals long before the adult condition is reached. In the mammal there is yet a third kindey. We have during the embryonic stage of the mammal always a well-developed excretory organ which corresponds to the middle or permanent kidney of the frog, yet during embryonic life the greater part of this temporary structure is entirely destroyed. It is dissolved away and vanishes, leaving only a few remnants of comparatively little importance in the adult. The new structure, the permanent kidney which we have, takes its place functionally. Large portions of the tissues, which arise in the embryo, are destroyed at the time of birth, and take no share in the subsequent development of the child. If we follow out with the microscope the various changes which go on in the developing body we see revealed to us a very large number of cases of death of tissues, followed by their removal. Thus the cartilage which exists in the early stages dies and is dissolved away, and its place is taken by bone. Those things which we know as bony elements of the skeleton in the adult, in the embryo exist merely as cartilage, but the cartilage is not converted into bone but it is destroyed and its place taken by bone. There is overlying the heart of a child at birth a well-developed gland known as the thymus. After childhood this undergoes a retrograde development; it becomes gradually absorbed and persists only in a rudimentary condition. "With the loss of the teeth occurring during infancy, you are familiar, and know that the first set of teeth are but for a short period, and are to be replaced by the permanent set. In very old persons we see a great deal of the bony material absorbed, and this absorption of the bone is a phenomenon which occurs at almost every period of the development. Portions of the epidermis or outer skin are constantly shed, as is well known, and the loss of hair and the loss of portions of our nails are so familiar to us that we hardly heed them. Of the constant destruction of the cells, which are found in the lining of the intestine, I have already spoken. At all times in the body there is a vast amount of destruction of blood corpuscles going on, a destruction which is physiologically indispensable, for the material which the blood corpuscles furnish is used in many ways. For instance, the pigment which occurs in the hair is supposed to be derived from the chemical substances the use of which the body obtains by destroying blood corpuscles. One of the most familiar instances of destruction is that of the tail of the tadpole. The young frog and the young toad during their larval stages live in the water and each of them is furnished with a nice tail for swimming purposes. As the time approaches for the metamorphosis of the tadpole into the adult, the tail is gradually dissolved away. It is not cast off, but it is literally dissolved, resorbed, and vanishes ultimately altogether.

It is evident that such a vast amount of destruction of living cells could not be maintained in the body without the body going entirely to destruction itself, were there not some device for making good the losses which are thus brought about. We find in fact that there is always a reserve of cells kept to make good the loss which it is essential should be made good. Some losses apparently do not have to be repaired, but the majority of them must be compensated for, and this is done by having in the body a reserve supply of cells which can produce new cells of the sort required. This leads us to consideration of the phenomenon of regeneration and of the repair of parts. These phenomena we can better take up later in our course, when we have dealt with the general processes of development and growth. From the study of regeneration we shall be able to confirm the explanation of old age, which I want to lay before you. This confirmation is so important that it will be better taken up in a separate lecture, than slipped in now when the hour is nearly by.

Old age, after what I have said, I think you will all recognize as merely the advanced and final stage of cytomorphosis. Old age differs but little in its cytomorphosis from maturity; maturity differs much from infancy; infancy differs very much indeed from the embryo; but the embryo differs enormously from the germ in its cytomorphic constitution. We know that in the early time comes the great change, and this fact we shall apply for purposes of interpretation later on. Cytomorphosis is then a fundamental notion. It gives us in a general law, a comprehensive statement of all the changes which occur in the body. None, in fact, are produced at any period in any of us except in accordance with this general cytomorphic law. There is, first, the undifferentiated stage, then the progressive differentiation; next there follows the degenerative change ending in death, and last of all the removal of the dead cells. Such we may conveniently designate as the four essential stages of cytomorphosis. This cytomorphosis is at first very rapid; afterwards it becomes slower. That is a significant thing. The young change fast; the old change slowly. We shall be able, when we get a little farther along in our study, to see that in differentiation lies the explanation of a great deal of biological knowledge, lies the explanation of our conception of cell structures; and in it also lies not only the explanation of the death of cells, but also, as it seems to me—and this is one of the points that I shall want particularly to bring forward before the close of the course—of general death, that which we mean by death in common parlance, when the continuation of the life of the individual ceases, and is thereafter bodily impossible. The explanation of death is one of the points at which we shall be aiming in the subsequent lectures of the course. Now we know that in connection with age there is always growth. I propose, therefore, in the next lecture, to take up the subject of growth. We shall arrive at some paradoxical conclusions, for it can be shown by merely statistical reckonings that our notion that man passes through a period of development and a period of decline is misleading, in that in reality we begin with a period of extremely rapid decline, and then end life with a decline which is very slow and very slight. The period of most rapid decline is youth; the period of slowest decline is old age, and that this statement is correct I shall hope to prove to you with the aid of tables and lantern illustrations at the next lecture.

  1. The illustration referred to is not reproduced in the text.
  2. The two figures of the bee's brain are not reproduced in the text.
  3. I. Death of Cells
    First. Causes of death.
    A. External to the organism:
    (1) Physical (mechanical, chemical, thermal, etc.).
    (2) Parasites.
    B. Changes in intercellular substances (probably primarily due to cells):
    (1) Hypertrophy.
    (2) Induration.
    (3) Calcification.
    (4) Amyloid degeneration (infiltration).
    C. Changes inherent in cells:
    Second. Morphological changes of dying cells.
    A. Direct death of cells:
    (1) Atrophy.
    (2) Disintegration and resorption.
    B. Indirect death of cells:
    (1) Necrobiosis (structural change precedes final death).
    (2) Hypertrophic regeneration (growth and structural change often with nuclear proliferation precede final death).
    Third. Removal of cells.
    A. By mechanical means (sloughing or shedding)
    B. By chemical means (solution).
    C. By phagocytes.
    II. Indirect Death of Cells
    A. Necrobiosis.
    (1) Cytoplasmic changes:
    (a) Granulation.
    (b) Hyaline transformation.
    (c) Imbibition.
    (d) Desiccation.
    (e) Blasmatosis.
    (2) Nuclear changes:
    (a) Karyorhexis.
    (b) Karyolysis.
    B. Hypertrophic degeneration.
    (1) Cytoplasmic:
    (a) Granular.
    (b) Cornifying.
    (c) Hyaline.
    (2) Paraplasniic:
    (a) Fatty.
    (b) Pigmentary.
    (c) Mucoid.
    (d) Colloid, etc.
    (3) Nuclear (increase of chromatin).