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Popular Science Monthly/Volume 71/November 1907/The Problem of Age, Growth and Death V

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

JAMES STILLMAN PROFESSOR OF COMPARATIVE ANATOMY, HARVARD MEDICAL SCHOOL

V. Regeneration and Death

Ladies and Gentlemen: In the last lecture I treated the conception I had formed of the processes of regeneration and told you that I looked upon the change which occurred first in the developing germ as one of rejuvenation. The process has for its technical name the segmentation of the ovum. The appearance of this segmentation process was illustrated to you by the pictures thrown upon the screen. Cytomorphosis is a term which we have frequently used in the course

PSM V71 D461 The segmentation of the ovum of ambystoma punctatum.png

Fig. 51. The Segmentation of the Ovum of Amblystoma punctatum, to show the earliest phases of development in the egg of a newt. After A. C. Eycleshymer.

of these lectures, and I have led you, I hope, to the appreciation of the idea that in cytomorphosis we have at least a part of the explanation of old age. We have learned that the young cells which are produced by the segmentation of the ovum in the body in large part changed into old cells, and also that old cells can not go back in their development and again become young; so that one might easily be led to the suspicion that there could be no possible new young, a conclusion obviously absurd, for there is a constant renewal of the generations. Some

PSM V71 D462 Segmentation of the ovum of planorbis.png

Fig. 52. The Segmentation of the Ovum of Planorbis, to show the earliest phases of development of the egg of a pond snail. Alter Carl Rabl.

device, therefore, must exist by which that which is young is perpetuated, for that which is old can not again become young, and of that device I should like to say something this evening.

As a preliminary to the discussion of this interesting phenomenon, it is necessary to say a few more words in regard to the nuclei. You recall that the units, out of which the body is constructed, the cells, consist each of a little mass of protoplasm with a central body called the nucleus; and you will, I hope, recall that the increase of the protoplasm and the subsequent differentiation of the cell we looked upon as the cause of old age, and the increase of the nucleus as the cause of youth, of rejuvenation. In addition to what has been said concerning the size of the nucleus, some further explanation is necessary, and that can best be given with the aid of some illustrations upon the screen. The first of the pictures will, I hope, serve to recall to your minds what I said in regard to the process of the segmentation of the ovum. Here is an ovum, No. 1, a single cell, but relatively of enormous size, the ovum or germ of a newt, and the plate illustrates to us the gradual process of division of the original single cell into a number of distinct cells, and each of these we call a segment, and the formation of them, segmentation, a name which we keep from the olden time when the process was first observed by some French investigators, because it is so descriptive of the appearance presented to the eye by the changes which are going on. Were we to name the process now we should certainly call it a process of cell production.

The next of our pictures shows us the eggs of a common snail, the Planorbis, a little fresh-water snail, the coils of which lie flat in one plane—hence its name. No. 1 is the original germ; No. 2 shows it about to divide into two; No. 3 is a side view; No. 4 a top view of the ovum with two segments; No. 5 is cleft into four segments; No. 6 into eight. Nos. 7 and 8 illustrate the further progress of the cell multiplication; No. 9 represents the under side of the same egg of

PSM V71 D463 Three sections through the segmenting of a mammal tarsius spectabile.png

Fig. 53. Three Sections through the Segmenting Ova of a Mammal, Tarsius spectabile. 1, ectoderm; 2, mesoderm; 3, entoderm; 4, Hensen's knot; 5, entoderm; 6, mesenchyma; 7, entoderm; 8, medullary groove; 9, ectoderm; 10, large motor neurone; 11, spinal ganglion; 12, mesenchyma; 13, cartilage; 14, Wolffian body; 15, kidney; 16, striated muscle; 17, heart muscle; 18, esophageal entoderm; 19, tracheal entoderm; 20, liver; 21, entoderm; 22, motor neurone; 23, spinal ganglion; 24, dermis; 25, hypodermis; 20, cartilage; 27, 28, Wolffian tubules; 29, pelvis of kidney; 30, heart muscle; 31, esophageal entoderm; 32, tracheal entoderm. After A. A. W. Hubrecht.

which the top is figured as No. 8. The number of cells (segments) is thus constantly increasing and already it is evident that they have become somewhat unlike in character. Were the picture still further magnified, we could see that in these cells a change is going on in the nuclei which, however, I can better demonstrate to you by means of the following picture, one which we saw in the last lecture. These are sections through the early developing germ of a mammal named Tarsius spectabile. It is a creature nearly related to the lemurs, having a special interest to naturalists, owing to the fact that in its early development it offers features of resemblance to man which are very striking and instructive. The plate is from a series of drawings made under the direction of Professor Hubrecht, the principal student of the development of this type of animal. Here (No. 1) we can see an early stage in which the germ consists of but a single cell, and at this point is the nucleus. Note its size and then compare it with the nuclei in Nos. 2 and 3 in which several of these cells, as they appear in a section, are represented. The cells themselves are now smaller because they have multiplied by the division of the original germ, but the nuclei in them are likewise smaller. And in the older stage, No. 3, where the number of cells has begun still further to increase, we see that there is another and more marked reduction in the size of the nuclei. Contrast the single nucleus of the early stage with the small nuclei of the later one, and notice how very striking is the change in the size. Thus during the early development of the individual, and it seems to be true of all animals, we find that there is an actual rapid reduction in the size of the nucleus. As we have learned that the proportion of the nucleus and the protoplasm is so important, we must attribute to this alteration in the dimensions of the nucleus great significance.

We have next a series of figures which have interested me very much and which I only recently secured as the result of studies I have been making in my own laboratory at the Harvard Medical School. These pictures are now shown publicly for the first time, and record a fact which, so far as I know, has never yet been clearly noted and recognized as important by any investigator. The four figures at the top represent four single nuclei taken from different parts of a rabbit seven and one half days after the commencement of its development. The second set of figures, 5, 6. 7 and 8. show nuclei from different characteristic parts of a rabbit embryo of ten days. Note, please, the size of these nuclei, the curious network of threads in their interior and the existence, generally more or less in a central position, of a mass of material which stands out conspicuously and represents a condensation of the nuclear stuff at that particular point. Such a central body is highly characteristic of these early stages. Next we come in the series of figures, from to 20, stretching across the screen in two lines, to a rabbit embryo of twelve and one half days. Instead of having nuclei of large size we have now nuclei which are obviously small. Instead of having nuclei which are more or less alike in appearance, we have now nuclei of great diversity. Every one of these figures, as you will readily see if you run your eye along from one end of the lines to the other, has a distinctive character of its own. In this period, then, of two and one half days, there has been a revolution in the character of the nuclei of the developing embryo. Where before the nuclei were alike, now they have become unlike. Two of these I

PSM V71 D465 Nuclei from rabbit embryos.png

Fig. 54. Nuclei from Rabbit Embryos. 1-4, age, seven and one half days. 5-8, age, ten days 9-20, age, twelve and one half days. 21-33, age, sixteen and one half days.

should like especially to call your attention to, because they are the nuclei of the nerve cells—this one, No. 11, from the spinal cord and the right-hand one, No. 10, from the cluster of nerve cells upon the root of a spinal nerve. Finally, we have the series of figures from a rabbit of sixteen and one half days represented in the two lower rows, 21 to 33. In these, if you will leave aside from consideration for the moment 22 and 23, which are obviously of a different size, all are now smaller than they were at twelve and one half days. Every one of the nuclei here represented is characteristic. We have here, for instance, nuclei of the excretory organ; a nucleus of the connective tissue; we have nuclei from the lining of the wind-pipe and the lining of the gullet. Every one of them differs from every one of the others pictured. But if we had drawings of a number of nuclei from the same part of the body and same kind of tissue, we should see that they would be essentially similar. We learn then that there is acquired a great diversity in the structure of the nuclei as well as in that of the protoplasm, of which we have seen so many examples in the previous lectures. You will recall, that as regards the size of cells the nerve cells present a noteworthy tion in that they differ according to the size of the animal; and their nuclei differ also, for as the cells become big the nuclei grow likewise. Here are nerve-cell nuclei in the rabbit of twelve and one half days not differing in their dimensions essentially from the nuclei of other types, but in the two lower figures, 22 and 23, we see nuclei corresponding to the cells of the rabbit at sixteen and one half days. These cells have begun to enlarge, to assume the greater dimensions of the nerve cells, which is characteristic of the rabbit; and accompanying the enlargement of the cells there has been an expansion of the nuclei also. But this does not affect, as you will readily see by the pictures upon the screen, the nuclei of any other sort of tissue, the nuclei of any other organ of the body.

"We must therefore add to our conceptions in regard to the relations of the nucleus and protoplasm, as quantitatively expressed, this further notion that there is during the early period of development an actual reduction in the size of the nucleus. When this reduction has taken place it is of course evident to any one at all acquainted with the principles of cytology that the cells are in a very different state from what they were in before. They are no longer such cells as they were when the nucleus was large, and the nuclei in the different parts of the body alike in character. Here the relations are fundamentally changed. We do not find that these nuclei ever get back from the complex variety of organization which they present to us in later stages to the earlier condition when they were all alike; yet only with cells of this uniform sort can development begin. We should therefore, if we reasoned only from the data which I have thus far presented to you, come to the conclusion that reproduction would be impossible, that the cells of the body, having been so changed, as we have seen, are no longer capable of returning backwards along the path they have journeyed; they can only remain where they are, or go yet further onward in the career of cytomorphosis. Nature, however, has met this difficulty by a way which we have only recently discovered. We are not yet sure that the way we have discovered is the only way, that it is the universal method in the case of all animals for accomplishing the purpose. The discovery of this method of providing for the perpetuation of youthfulness from one generation to another, the youthfulness of the cell of man, is due to the investigations of Professor Nussbaum, of Bonn. The theory, which he put forward, has been verified by subsequent examinations and investigation, and confirmed, I am glad to say, in part by some very interesting and careful observations which have been made here in Boston. Perhaps the very best confirmation of all is the recent extension of our knowledge in regard to this theory which comes from the investigations of Dr. B. M. Allen, made at Madison, on the process as we find it in the developing turtle. It is really essentially a very simple tiling. Nature seems to take some of the cells which are in the primitive condition, with the protoplasm still undifferentiated and the nucleus of the embryonic or simple organization, and hold them apart from the rest of the body, not separating them so that they come off and leave the body, but so that they have a different history; so that they escape the change which the other cells of the body must pass through. These cells of a simpler character are gathered together, kept asunder, and not allowed to progress in the development of all the cells which form the body proper. We have learned, for instance, that in the development of the dog-fish very early, before any organs exist, cells are formed into a cluster. They lie by themselves, are easily recognized under the microscope, and they have obviously the primitive character which I have endeavored to explain to you. And they remain such. Meanwhile as development progresses, all the remaining cells—all those not part of these clusters, pursue their proper careers, become differentiated; but the cells in the clusters do not change for a long period. Later as the organs become differentiated, we can recognize in the direct descendants of these cells, which have been traced from stage to stage so that their history is known with certainty, those cells which in the adult we call the germ cells, and which are to serve for the reproduction of the species. These cells are set apart at all periods. They represent germinal matter which is withheld from the metamorphosis which the rest of the body undergoes. They have a continuous history. Hence we bestow upon this method, under the conception that it is applied to secure propagation of the species, the term—theory of germinal continuity. It is the theory of hereditary transmission which I think is now universally held by all competent biologists. Our study of nuclei and of their relations to protoplasm serves to clear up in our minds, it seems to me, to some degree at least, the necessity which really exists for this device of germinal continuity, of the setting apart of certain cells of the rejuvenating sort, of the young sort, of the embryonic type (the term you apply to them matters little), which cells are those used to produce the new offspring of the next generation. All this, of course, fits perfectly with the doctrine which I have been telling you of again and again in this course of lectures, that the progress of differentiation is always in one direction and ends in the production of structure which, if it is pursued to its legitimate terminus, results in the degeneration and death of the cell. Obviously such a set of changes as I have thus indicated can not produce the sort of a cell which is necessary for reproduction.

I wish there were time to enter more fully into this question of the size of nuclei, for there is much which might be said concerning it. This much more, however, ought to be said to you—that the problem of the size of nuclei is by no means a simple one. It has been found, for instance, in the experiments made upon some of the simple algæ, the so-called Spirogyra, which every elementary student of botany probably has looked at in the laboratory. that by certain artificial conditions, as made in the experiments of Professor Gerassimow, the size of the nucleus can be changed in the cells, and when the size of the nucleus is changed, the size of the cell alters also. And again, we know that the nucleus provides certain chemical supplies for the life and functioning of the cells. This is very strikingly the case, for instance, in regard to the cells which secrete. These, when they give off the material which they have accumulated in their protoplasm as a preparation for the act of secretion, are found not only to reduce the bulk of their protoplasmic bodies, but the bulk of the nuclei as well. And we know again that the size of nuclei may be changed by somatic conditions, by food supply, so that in every generalization reached by the study of the size of nuclei, we must be very circumspect, and not fancy too easily that we have reached a safe conclusion unless we have taken into consideration all the possible factors by which the size may have been varied.

In what I have said to you hitherto in regard to the power of growth, I have directed your attention chiefly to the power of growth as it exists in a cell in consequence of that cell's condition. When the cell is in the young state, it can grow rapidly; it can multiply freely; when it is in the old state it loses those capacities, and its growth and multiplication are correspondingly impeded, and if the organization is carried to an extreme, the growth and the multiplication of the cell cease altogether.

We find, however, that there is something a little more complicated yet to be considered, for it is not merely a question of the capacity of the cells, but also of the exercise of that capacity, which we must deal with. Here comes in a factor which we learn from the study of regeneration. The phenomena of regeneration are very important and very instructive. We shall come to those in a moment. It will make our study of regeneration clearer, more significant, I think, if we pause for a moment to consider certain fluctuations in the natural development of the organism. We see, for instance, in the brain that early the cells begin to assume the character of nerve cells and that thereafter their multiplication ceases. But, curiously, there will be a spot in the spinal cord, for example, where the change of the cells into nerve cells has not taken place, and from that growth will go on. Cells will migrate from that spot and reach their ultimate destination. When the child is born it is very incapable of movement. There is scarcely more than the power of twitching about in a disorderly fashion. Its muscles can contract, to be sure, but any sort of motion that implies a harmonious working together of various muscles, the baby at birth is quite incapable of. This phenomenon is doubtless due to the fact that the cerebellum, the small brain, is as yet imperfectly developed. If we examine the brain of the child at birth. we find at the edge of the cerebellum a line along which the production of new cells is going on. These new cells migrate over the surface of the cerebellum without changing at all into nerve cells. The}-form a distinct layer which is well known to every investigator of brain structure, and presently after birth these cells accomplish a second migration, but in a different direction. Instead of moving in a constant current over the surface of the brain, each one takes a vertical pathway from the surface down towards the interior of the cerebellum; and arrived there it changes and becomes a nerve cell, or at least a part of them do; and with that the machinery of the cerebellum is complete. Thus, structurally, the cerebellum at birth is an uncompleted organ. Now, the cerebellum is that portion of the brain which regulates the combination of muscular movements, which secures that which the physiologists term coordination of movements, and it is not until the cerebellum has been perfected that it can perform this function. Were there not some provision of this special sort for allowing cells to be produced and added to the brain, the full complexity of the brain could not be attained, because after the cells have begun to change into nerve cells they lose their power of multiplication, and this is a device very exquisite in its working to supply to the brain the requisite number of cells to give it its full measure of complexity.

Another instance of the reservation of cells of a simple type is afforded us by the skin, al)out which I shall have something more to say in a few moments when we speak of the process of regeneration. It is not only in the period of childhood, and not only in the cerebellum, that we find cells exist such as I have just described to you, but it is in other parts of the body also and at other periods of life that we find the like phenomena; and in part I have already referred to these. You remember I told you in a previous lecture there is always in the body, even at the extreme of life, a store of cells of the young type, which is garnered in the marrow of the bones. The cells in question can multiply, and their descendants in part undergo a change in consequence of which they are converted into blood corpuscles. The undifferentiated or young cells are preserved in the marrow precisely for the purpose of making up the necessary number of blood corpuscles to replace those which are lost either by accident or in consequence of normal physiological processes. I mentioned to you that in the lining of the intestine there is a constant loss of cells and we find in every simple gland of the intestine, in every little gland of the stomach, a center for cell production, a center where there is a group of cells which are not differentiated, but retain their simple organization.

I could multiply these instances almost indefinitely, but perhaps it will be better to call your attention to an illustration of quite a different sort. We know that in order to have a very complex organization, the number of cells in the body must be very large indeed. Obviously a small insect, a mosquito or a little beetle, whatever it may be, is not big enough to have a great many cells; and, unless it has a great many, it can not attain the differentiation of complicated organs such as we possess. Now, the lower animals are born, so to speak, early, and as soon as they hatch out. they have to support themselves. We see that, for instance, in caterpillars. They are born very little creatures, but each caterpillar must look out for itself, obtain its own food, move about to that food, must, when the food is swallowed, digest it, and must carry on the correlated functions of secretion and excretion; it must breathe. In order to do all this the larva, or young caterpillar, to follow our special instance, must have some differentiation already established; but, as we have already learned, differentiation impedes growth. In other words, in such a larva the multiplication of cells is held back by the very demands of the conditions of its existence. If it is to have organs which are to function, it must have differentiated parts, and, if it is differentiated, its growth power must be sacrificed.

Now how has nature proceeded in order to produce a higher type of animal, one in which the number of cells is much greater? Very ingeniously. She provides the developing organism with a food supply which it carries itself. If, for instance, you recall the egg of the salamander, which I showed you upon the screen, you will remember that that is a structure of considerable size, and its size is due to the accumulation of food material, material which we designate by the term yolk granules, which lie in the living protoplasm of that germ. This supply of food is so great that it will last the organism a considerable period. While it is growing it has nothing to do but to digest that food supply which it already possesses. It does not have to exert itself to obtain it, and no further digestive process is necessary than that inherent in all living protoplasm. So the young salamanders develop in a most advantageous condition, and can actually produce a much greater number of cells because it is possible, with this internal food supply, for the growth to go on only with the cells of the embryonic or youthful type for a considerable period, and then, when their number has considerably increased, steps in the process of differentiation.

In the higher animals this accumulation of food for the nourishment of the germ is carried yet further. As you know, the egg of the bird is much bigger than that of the salamander, and in the highest animals, in the mammals, there are other special contrivances which nature has introduced to secure ample and adequate nourishment of the developing germ. There the perfection of the process is made yet greater and in these forms there is a long period during which the production of cells goes on; the cells all remain simple, and by the time they begin to change the number of cells is so great that the possibilities of an infinite variety, almost, of peculiarities in them are given, and there are cells enough to allow this variety to be worked out. This we call the embryonic type of development.

We see, therefore, that nature has recognized a restriction which she herself has put upon development, the restriction which obliges development, if it is to be ample, to prolong the accumulation of the undifferentiated cells. In response to that condition, she substitutes for higher types of animal that development which we call embryonic, leaving for the lower type that which we call larval. Thus we see in the growth and formation of the higher animals and in the history of the comparative development of the animal kingdom, fresh illustrations of the great importance of the young type of cells.

We can see the same thing also in regard to regeneration. The regenerative process depends to a large extent upon partial differentiation, or even upon its total absence. Regeneration is a most interesting and wonderful process. I took pains only this afternoon to look at that famous classic by the Dutch Abbe Trembley on hydroids or polyps as he calls them. "The Fresh Water Polyps." a book published in 1744, was well printed, and on such good paper that it looks to-day

PSM V71 D471 Vignette from classic memoir of trembley.png

Fig. 55. Vignette from Trembley's Classic Memoir, representing Trembley making his experiments of regeneration in fresh-water polyps.

almost like a new book. He made the curious experiment of cutting one of these minute fresh water polyps—they are perhaps an eighth of an inch long—in two, and made the startling discovery that each half of the polyp would make up what the other half had deprived it of: each half, in other words, would become a new polyp. That which was lost was regenerated. After him came a series of yet more remarkable experiments by the famous Italian naturalist, Spallanzani, one of the masters of experimental research, and he discovered that regeneration was a property which was not peculiar by any means to polyps, but existed in the earth-worms, and even among vertebrates; for he it was who discovered that if the head of an earthworm be cut off, the worm will form a new head with a new brain and a new mouth. He first discovered that if you cut off the tail of a salamander a new tail will grow out. He it was, moreover, who discovered that this power of replacing the lost part is greater in the young—greater in the earlier stage than in the later. This indicates in a general way the nature and process of regeneration. We have many kinds of regeneration; we may have that of the single 'cell or that of the whole organism.

We pass now to the next of our slides, which represents a creature of the kind called Stentor. It is a single cell. Here is the nucleus of

PSM V71 D472 Stentor.png

Fig. 56. Stentor.

the cell; its protoplasmic body is large, and something of the structure of this I have told you in a previous lecture. A German investigator, Professor Gruber, has succeeded in dividing one of these Stentors, a unicellular creature, animalcule, common in fresh water, into three parts in such a method of cutting as is illustrated by the figure on the left. Each of the three parts will then restore itself and become a complete Stentor. In such experiments the protoplasm over the nucleus begins to grow; gradually the original form is again assumed; the creature grows larger and larger, until each piece acquires the parent size, and, so far as we can see with the ordinary microscopic examination, identically the parental structure. That which was lost has been regenerated. We learn, then, that regeneration is a faculty which a single cell, a single unit, may possess.

Our next picture demonstrates a similar phenomenon. These are muscle fibers which have been injured. Now every muscle fiber contains in its interior its contractile substance, in regard to which I have already spoken to you, but it also contains a certain amount of substance which is still undifferentiated protoplasm. Now when a

PSM V71 D473 Striated muscle fibers in process of regeneration.png

Fig. 5. Striated Muscle Fibers is Process of Regeneration.

muscle fiber of this sort is injured, we find that the muscular structure, properly so called, will in many cases quite disappear, but then the protoplasmic material, which is the undifferentiated substance, will begin to grow, and the nuclei will begin to multiply. This may happen at the end of a muscle fiber, producing there a considerable mass of protoplasm, with nuclei multiplying in it, or we may find a chain of nuclei, each with its separate court of protoplasm body: such nuclei will multiply. When the increase of the undifferentiated protoplasm has gone on far enough, the injured muscle will produce again the muscular substance proper—the contractile fibrils. Muscular fiber, in other words, can be regenerated by itself.

A similar thing to this happens when a nerve is cut across. The nerve fiber, which is connected with the nerve cell from which it arose, is capable of growing out again. It can regenerate itself, and that is a well-known phenomenon, and in many surgical cases it becomes a phenomenon of very great importance.

Let us go back to another familiar figure. Here is represented the lining layer of the œsophagus with the cells composing it, the upper bones being horny, the lower ones those which are capable of active growth. We are rather dull. We do not often stop to think about things. We buy a new horse which comes from the country, has never seen a train; drive him to the station, and are frightened, perhaps, because the horse himself is so much alarmed—possibly have a narrow escape because of the excitement which his first sight of a train causes him. But that horse, after a few months' discipline, will scarcely turn his ear, much less his head, to look at the train which a short time before so frightened him and held his attention that nothing else could get into his mind save the fright that train gave him. So we, too, act a good deal like the horse. We see a thing the first time and it surprises us; the next time it seems like an old acquaintance, a thing

PSM V71 D474 Section of the ephitelial lining of the human esophagus.png

Fig. 58. Section of the Epithelial Lining of the Human Œsophagus.

familiar and therefore unregarded. I say this apropos of the skin. How many of you have thought what the lesson of the skin is in regard to the power of growth? Spring is coming; we shall soon be taking to our boats, rowing or canoeing, and the first day we do so doubtless we shall have blisters upon our hands, and the outer part of the skin, raised by the blister, will probably fall off and be lost altogether. The softer, underlying skin will be exposed, will be sensitive and uncomfortable for a while, but soon the cells behind the surface will assume a horny character, the cells underneath will grow and multiply, and presently the wound will be healed over. Did you ever stop to think that that means that there is a reserve power of growth in the skin all the time? always ready to act, to come forward, waiting only for the chance, and that there is besides something which keeps it in, which holds it back, which stops it? We call this stopping physiological function—inhibition; we say that the growth of the skin is inhibited; though in the deep part of the skin all the time there are the cells ready to grow as soon as that power of inhibition is taken away; while it is active they will not grow. The simple blister tells us all that. There is, then, a power of regulation which expresses itself in this inhibitory effect. When a salamander has its tail cut off by the experimenter and the new tail grows, just enough is produced. The new tail is like the old. The tissues grow out until the volume of that which is lost is replaced, and then they stop. But if the tail should be cut off again, regeneration would occur again. The experiments may be repeated many times over. It indicates to us that always the growing power is there, but it is held in check. What that check may be is one of the great discoveries we are now longing for. The discover}', when made, is likely to prove of great practical importance. The phenomenon of things escaping from inhibitory control and overgrowing, is familiar. Such escapes we encounter in tumors, cancers, sarcoma and various other abnormal forms of growth that occur in the body. They are due to the inherent growth power of cells kept more or less in the young type, which for some reason have got beyond the control of the inhibitory force, the regulatory power which ordinarily keeps them in. No picture of the growth or development of the living animal would be complete if it confined its attention only to the power of growth in relation to cytomorphosis. It must also include the contemplation and study of this regulatory power of the organs. Experiments are being made in many places, minds are at work in many laboratories upon this problem of regulation of structure and growth. Much is to be hoped from such researches; not merely insight into the normal development, but insight also into the abnormal. Nothing, perhaps, is more to be desired at the present time than that we should gain scientific insight into the regulatory power which presides over growth. It would be of immense medical importance. Could we understand it, and could we from our understanding derive some practical application of our scientific discoveries in this field, we could say of it justly that it was as noteworthy a contribution to medical knowledge as the discovery of the germs of disease, and would doubtless prove equally beneficial to mankind. Although, then, the study which I have been laying before you must necessarily seem in many respects abstruse and far away from practical applications, we learn that it is not really so, and that it leads by no very remote path to the consideration of problems the useful applications of which are immediately obvious to every one.

We find in the process of regeneration that it is always the young cell which plays the principal part. This is beautifully illustrated in the picture upon the screen. There is a little creature, which many of you have seen in the garden, consisting of joints, which rolls itself up into a little ball, and therefore is often called the "pill-bug." It is not, however, an insect or a bug, properly so-called, but belongs to a family of crustaceans. It has on its head a little feeler which we call the antenna. The particular kind of arthropod, the antenna

PSM V71 D476 Oniscus antenna sections during regeneration after amputation.png

Fig. 59. Sections through the Antenna of Oniscus in Various Stages of Regeneration after Amputation. After Ost.

of which has been studied and drawings of it made to furnish us this plate, is known by the name of Oniscus. In his researches the experimenter. Dr. Ost, cut off the antenna in the middle of a joint and found that it rapidly healed over. Here is pictured the process of healing going on. Part of the antenna has been cut off in this case, the wound was healed over here, No. 1, a, the new tissue has begun to grow, No. 2, b, and the cells at this point are very simple in character. They spread out and grow, and then, within the interior of the hard shell of the feeler, a retraction of the substance occurs, and the new growing cells within this space gradually begin to shape themselves out. No. 3, b, and we see presently an accumulation of cells which is assuming a definite form, No. 4, b, that in the next figure has clearly become the promise or beginning of a new terminal joint, Fig. 60. The minute study of this process has shown that the regeneration depends practically exclusively upon the cells of the young type, and that after they have grown out and accumulated here in this manner, No. 3, b, some of them undergo differentiation, becoming muscle cells; others change in the manner indicated here, where we see a commencing alteration of the nuclei, PSM V71 D477 Section through a regenerating antenna of oniscus.pngFig. 60. Section through a Regenerating Antenna of Oniscus. After Ost. Advanced stage, in which the young new joint is already shaped within the old shell. a, cicatricial tissue; b, regenerated tissue: j, new joint; cu, cuticula (old shell). Magnified. which is further accented in Fig. 60, and leads to such a grouping of the cells that the glands, which were originally present there, are also reproduced. The regenerative process, then, clearly illustrates to us from another point of view the great importance of the young type of cells.

This completes the evidence which my time permits me to lay before you in order to convince you that really the young type of cells is physiologically and functionally important, that it really does possess the power of growth such as I have attributed to it.

We will pass now to another part of our subject, with which the lecture will close. Age represents the result of a progressive cytomorphosis. We have learned that of cytomorphosis death is the end, the culmination. It is a necessary result of the modification and change of structure which goes on in every individual of our species and of all the higher animals. We are familiar with the death of cells. It occurs constantly and, as I have endeavored to explain to you, it plays a great part in life. It promotes the performance of various functions which are of advantage to the body as a whole, which could not be accomplished without the death of some cells. But the death which we have in mind when we speak ordinarily of death is something different from this. It is the death of the whole. But even the death of the whole has its strange complications. A great deal of our knowledge of the functioning of the body is due to the fact that the parts do not die when, as we commonly say, the body as a whole, the individual, is dead. The organ is alive and well. One of the most impressive sights which I have ever seen has been the sight of the heart of a quadruped, a dog, continuing to beat after it had been taken out from the body. The dog was dead—the rest of his body was dead—but the heart lay upon the physiologist's table beating. The experimenter could supply it with the necessary circulation. He could give stimuli to it, and under these favorable conditions make important discoveries in regard to the functioning of the heart. So too I myself made experiments upon a muscle once part of a living dog, separated entirely from the parent body, supplied with its own artificial circulation, and from those experiments was able to discover some new unexpected results in regard to the nutrition of the muscle, and the changes which chemically go on in it. This over-living, then, of the parts of the body, their separate life, is something which we must familiarize ourselves with, and the great importance of which we must carefully acknowledge, for much of the benefit which the medical practitioner is able to render to us and to our friends to-day is due to the knowledge which has been derived experimentally from the study of the over-living or surviving parts of a body which as a whole was dead.

Death is not a universal accompaniment of life. In the lower organisms death does not occur as a natural and necessary result of life. Death with them is purely the result of an accident, some external cause. Natural death is a thing which has been acquired in the process of evolution. Why should it have been acquired? You will, I think, readily answer this question if you hold that the views which I have been bringing before you have been well defended, by saying that it is due to differentiation, that when the cells acquire the additional faculty of passing beyond the simple stage to the more complicated organization, they lose something of their vitality, something of their power of growth, something of their possibilities of perpetuation; and as the organization in the process of evolution becomes higher and higher, this necessity for change becomes more and more imperative. But it involves the end. Differentiation leads up, as its inevitable conclusion, to death. Death is the price we are obliged to pay for our organization, for the differentiation which exists in us. Is it too high a price? To that organization we are indebted for the great array of faculties with which we are endowed. To it we are indebted for the means of appreciating the sort of world, the kind of universe, in which we are placed. To it we are indebted for all the conveniences of existence, by which we are able to carry on our physiological processes in a far better and more comfortable manner than can the lower forms of life. To it we are indebted for the possibility of those human relations which are among the most precious parts of our experience. And we are indebted to it also for the possibility of the higher spiritual emotions. All this is what we have bought at the price of death, and it does not seem to me too much for us to pay. We would not, I think, any of us, wish to go back to the condition of the lowly organism which might perpetuate its own kind and suffer death only as a result of accident in order that we might live on this earth perpetually; we would not think of it for a moment. We accept the price. Death of the whole comes, as we now know, whenever some essential part of the body gives way—sometimes one, sometimes another; perhaps the brain, perhaps the heart, perhaps one of the other internal organs may be the first in which the change of cytomorphosis goes so far that it can no longer perform its share of work, and failing, brings about the failure of the whole. This is the scientific view of death. It leaves death with all its mystery, with, all its sacredness; we are not in the least able at the present time to say what life is. still less, perhaps, what death is. We say of certain things—they are alive; of certain others—they are dead; but what the difference may be, what is essential to those two states, science is utterly unable to tell us at the present time. It is a phenomenon with which we are so familiar that perhaps we do not think enough about it.

In the next lecture there will be some other general aspects of our subject to present to you, and a formulation of the general conclusions towards which all the lectures have aimed.