Columtim Winihtvsiitf "^^ CoHege of ^fipfiitians; anb ^urgeonaf 3^eferente l.itirarj> l;t Digitized by tlie Internet Arcliive in 2010 witli funding from Open Knowledge Commons (for the Medical Heritage Library project) http://www.archive.org/details/problemofagegrow1908mino THE SCIENCE SERIES Edited by Edward Lee Thorndike, Ph.D., and F. E. Beddard, M.A., F.R.S. 1. The study of Man. By A. C. Haddou. 2. The Qroundwork of Science. By St. Geo^. e. Mivart. 3. Rivers of North America. By Israel C. Russell. 4. Earth Sculpture, or ; The Origin of Land Forms. By James Geikie. 5. Volcanoes ; Their Structure and Significance. By T. G. BONNEY. 6. Bacteria. By George Newman. 7. A Book of Whales. By F. E. BtDDARo. 8. Comparative Physiology of the Brain, etc. By Jacques Loer. 9. The Stars. By Simon Newcomb. 10. The Basis of Social Relations. By Daniel G. Brinton. 11. Experimer>-s on Animals. By Stephen Paget. 12. Infection and Immunity. By George M. Sternberg. 13. Fatigue. By A. Mosso. 14. Earthquakes. By Clarence E. Dutton. 15. The Nature of Man. By Elie Metchnikoff. 16. Nervous and Mental Hygiene in Health and Disease. By August Forel. 17. The Prolongation of Life. By Elie Metchnikoff. 18. The Solar System. By Charles Lake Poor. ig. Heredity. By J. Arthur Thompson, M.A. 20. Climate. By Robert DeCoukcy Ward. 21. Age, Growth, and Death. By Charles S. Minot. i2. The Interpretation of Nature. By C. Lloyd Morgan. 23. Mosquito Life. By Evelvn Groesbeeck Mitchell. 24. Thinking, Feeling, Doing. By E. W. Scripture. J^or list of works in preparation see end of this volume. TLbc Science Series EDITED BY JE^)war^ Xee ■JEboiiiMfte, |pb.S>. AND 3f . E. 36eB6ar6, m.U., jf.tR.S, The Problem of Age, Growth, and Death The Problem of Age, Growth, and Death A Study of Cytomorphosis Based on Lectures at the Lowell Institute March, 1907 By Charles S. Minot LL.D. (Yale, Toronto), D.Sc. (Oxford) James Stillman Professor of Comparative Anatomy in the Harvard Medical School President of the Boston Society of Natural History Illustrated G. P. Putnam's Sons New York and London Zbc IRnicl^erbocfier piess 1908 Copyright, igo8 BY CHARLES S. MINOT Ube 1kn(cfterbocf?ec iprcss, mew KorS ANGELO iNIOSSO SENATOR OF THE KINGDOM OF ITALY PROFESSOR OF PHYSIOLOGY AT THE UNIVERSITY OF TURIN THIS VOLUME IS DEDICATED BY THE AUTHOR CONTENTS PAGE INTRODUCTORY LETTER TO SENATOR MOSSO . . . vii CHAPTER I THE CONDITION OF OLD AGE ...... I CHAPTER II CYTOMORPHOSIS: THE CELLULAR CHANGES OF AGE . . 38 CHAPTER III ,'J THE RATE OF GROWTH ....... 86 CHAPTER IV DIFFERENTIATION AND REJUVENATION .... I3I CHAPTER V REGENERATION AND DEATH ...... 169 CHAPTER VI THE FOUR LAWS OF AGE ....... 2x8 APPENDIX I GROWTH OF RABBITS ....... APPENDIX II GROWTH OF CHICKENS 253 258 APPENDIX III DEATH OF PROTOZOA ........ 262 vi - CONTENTS PAGE APPENDIX IV LONGEVITY OF ANIMALS . 266 APPENDIX V THEORY OF LIFE . 267 APPENDIX VI THE AGE-RECKONER ........ 273 INDEX 275 ILLUSTRATIONS FIGURE 1. Two Human Vertebral Columns 2. Photograph of Chevreul .... 3. Photograph from a Child at Birth 4A. ^ f Child at Birth 4B. >• Ribs and Sternum -< Child at Seven Years 4c. J V Adult, Thirty Years 5. Section of the Head of the Thigh Bone of a Man 6. Section of the Head of the Thigh Bone of a Woman 7. Cells from the Mouth of the Salamander 8. Example of a Syncytium . . . • • 9. Three Transverse Sections through a Rabbit Embryo of Seven and One-Half Days 10. Portion of a Transverse Section of the Spinal Cord of a Human Embryo of Four Millimetres 11. Copy of Original Figure from the Memoir of Deiters 12. A Large Cell from the Small Brain of a Man 13. Various Kinds of Human Nerve Cells 14. Sections of Four Sorts of Epithelium . 15. To Show the Orbital Gland of a Dog 16. Two Sections of the Pancreatic Gland of a Dog 17. Section of the Human Skin, Made so that the Hairs are Cut Lengthwise ..... 9 I 2 40 44 46 50 51 53 55 56 58 59 viii ILLUSTRATIONS i8. Cross-Section of the Root of a Hair . 19, Cross-Section of a Lingual Muscle Fibre of the Moccasin Snake ...... 61 62 62 63 66 20. Part of a Muscle Fibre of the Human Tongue . 21. Section of a Human Retina .... 22. Motor Nerve Cells of Various Mammals 23. Group of Five Nerve Cells from the First Cervical Ganglion of a Child at Birth .... 68 24. Group of Four Nerve Cells from the First Cervical Ganglion of a Man Dying of Old Age, at 92 Years 69 25. Life History of Blood Corpuscles, Rabbit Embryos . 78 26. Four Tadpoles of the European Frog ... 88 27. Curves Showing the Growth of Boston School Children in Height and Weight . . . . .91 28. Curves Showing the Daily Percentage Increments in Weight of Male Guinea- Pigs .... 94 29. Curves Showing the Daily Percentage Increments in Weight of Female Guinea-Pigs .... 96 30. Curves Showing the Length of Time Required to Make Each Successive Increase of Ten per Cent, in Weight by Male Guinea-Pigs . ... 97 3 r. Curves Showing the Length of Time Required to Make Each Successive Increase of Ten per Cent, in Weight by Female Guinea-Pigs .... 98 32. Curves Showing the Growth of Man from Birth to Maturity 99 33. Curves Showing the Daily Percentage Increments in Weight by Male Chickens 10 1 34. Curves Showing the Daily Percentage Increments in Weight by Female Chickens .... 102 ILLUSTRATIONS ix 35. Curve Showing the Daily Percentage Increments in Weight by Male Rabbits .... 2,6. Curve Showing the Daily Percentage Increments in Weight by Female Rabbits .... 37. Yearly Percentage Increments in Weight by Boys, Reckoned by M. Miihlmann 38. Yearly Percentage Increments in Weight by Boys after H. H. Donaldson .... 39. Yearly Percentage Increments in Weight by Girls Reckoned by M. Miihlmann 40. Yearly Percentage Increments in Weight by Girls, after H. H. Donaldson 41. Yearly Percentage Increments in Weight by Boys and Girls 42. Ten Stages of the Developing Chick 43. A Chick Removed from an Egg after an Incubation of Ten Days and Two Hours 44. Fourteen Stages of the Developing Rabbit 45. Percentage Increments up to Birth in Man by Lunar Months, after Miihlmann .... 46. Cells from the Mouth of the Salamander . 47. Three Sections through a Rabbit Embyro of Seven and One- Half Days ..... 48A. Entamoeba Histolytica, Highly Magnified . 48B. Preserved Specimen of Entamceba Histolytica 49. Tertian Malarial Parasite ..... 50. Trypanosoma Lewisi ...... 51. Stentor Coiruleus ...... 52. Various Kinds of Human Nerve Cells 103 105 109 no 113 114 116 119 121 123 127 136 137 139 140 141 145 ILLUSTRATIONS 53. Part of a Human Muscle Fibre 54. Sections from an Orbital Gland of a Dog . 55. Diagram of Three Cells of a Salivary Gland 56. Embryonic Syncytium ..... 57. Amoeba Proteus ...... 58. Sections of Three Ova in very Early Stages 59. Progressive Segmentation of the Ovum 60. The Segmentation of the Ovum of Planorbis 61. Nuclei from Rabbit Embryos .... 62. Section across the Posterior Part of an Embryo Dog-fish ....... 63. Section of the Cerebellum of a Child of Thirteen Days 64A. Section of a Lens of the Eye of a Chick of Sixty-eight Hours' Incubation ...... 64B. Section of a Lens of the Eye of a Chick of Ninety-six Hours' Incubation ...... 65 66 67 68 69 70 71 72 73 Section of a Gland of the Large Intestine of an Adult Cat ......... Vignette from Trembley's Classic Memoir Stentor ......... Striated Muscle Fibres in Process of Regeneration Section of the Epithelial Lining of the Human CEsophagus ....... Longitudinal Sections through the Antenna of Oniscus Section through a Regenerating Antenna of Oniscus Portion of the Outer Wall of a Primitive Muscular Segment of a Cat Embryo ..... As;e-Reckoner ....... PAGE 147 148 148 162 164 173 176 182 187 190 190 193 198 199 203 208 209 220 272 INTRODUCTORY LETTER TO SENATOR MOSSO My dear Mosso : It is now over a third of a century since we were together in Leipzig as fellow-workers in the laboratory of Professor Carl Ludwig, on whom we look back as the greatest teacher of the art of scientific research whom we have ever known. He was a master of both the two great methods of biological study — observation and experiment. From him we learned to regard the living organism as an apparatus, of which it was necessary to learn both the construction and the working, and always to seek the explanation of the working on the basis of the construction. Al- though we have followed different lines of inquiry, the fundamental conceptions taught us by Ludwig have remained dominant. I look with admiration upon the number and importance of your scientific achievements. The pupil has proved himself worthy of the master, and has taken a master's place. You will find in this volume, I trust, evidence of Ludwig's continued influence upon my work, and of my effort to follow upon a lesser scale your ex- ample. The years which have passed since those xii INTRODUCTORY LETTER TO SENATOR MOSSO delightful student days have brought many changes, and have transformed us into members of the older generation. Therefore, I hope that you will regard the dedication of this volume on age to yourself as not inappropriate. As I write I recall our parting in the forest of Fontainebleau, our meeting on the glacier above Zermatt, our paddling together in a canoe on an American lake along the edge of the primeval forest, and many other experiences which we have shared. These were in our younger days, and now our interest in what is essential among the effects of age has a personal as well as a scientific foundation. This book deals with a series of important biologi- cal problems, yet it is essentially a study of a single phenomenon, — the increase in the amount of proto- plasm. The increase to be considered is not that which takes place at large in the body of the growing animal, but that which takes place within the limits of single cells, and occurs in such a manner that the proportion between the cell-body and the nucleus in volume, or bulk, is changed — the cell-body becoming relatively either larger as more frequently happens, or smaller, as happens in special cases. By the study of the proportionate volumes of the nucleus and the cell-body we can demonstrate, I be- lieve, certain laws governing that proportion, and prove that the variations of the proportion establish conditions which are fundamental to the correct con- ception of the problems of growth, differentiation, death, and sex. It is my endeavour, by following the INTRODUCTORY LETTER TO SENATOR MOSSOxni precepts of Ludwig, to prove the existence of another set of correlations between the structure of cells and their function, which hitherto has been unrecognised. The primary correlation of the variations in pro- portions, which can be demonstrated, is with the age of the organism. Accordingly, the investigation of age and growth occupies a large share of the volume. The subjects discussed in this book have received in part, hitherto, relatively little attention from bio- logists, hence the scientific literature dealing explicitly with them is rather scanty, although there are almost innumerable observations recorded in various writ- ings, which have a bearing on the problems to be solved. Under these circumstances I have been forced, necessarily, to rely almost exclusively upon my own investigation ; accordingly, the conclusions have a personal character in the sense that they have not yet been subjected to the critical judgment of bio- logists. Nevertheless, I hope that they will commend themselves to you. My own active interest in growth as a biological problem goes back twenty-nine years, when I pub- lished an article on " Growth as a Function of Cells," ^ followed by another, "On Certain Laws of Histo- logical Differentiation."^ These two papers, however, were of a somewhat theoretical character. Feeline strongly the necessity, which I should feel still more ' Proceedings Bosto7i Soc. Nat. Hist., xx., igo (1879). ^ Ibidem, p. 201. x\v IXTRODUCTORY LETTER TO SENATOR MOSSO strongly now, of getting to direct facts, I started a series of observations on the growth of animals, which have been continued for a long period, during which the research has expanded far beyond its original scope. While carrying forward my experi- ments on orrowth, various conclusions sueafested them- selves ; some tentative, others more or less definite. These have been partially and briefly published at various times.^ To review these publications now would serve little purpose beyond possibly establish- ing the claim of priority, and I will therefore merely enumerate them. Moreover, in the course of the following pages the more important results contained in these earlier papers are brought together. My experiments on growth led to a memoir ^ published in 1891, in the English Journal of Physiology. It dealt with the growth of guinea-pigs and is to be regarded as the starting point or foundation of the present work. Since then the experimental work has been continued, and data concerning the growth of other animals collected. They are given in the course of the following pages. ' "Death and Individuality," y^iwrw. Sci., vii., Ti-TJ (1S85), reprinted, Science, iv., 72-77. " Researches on Growth and Death," Proc. Soc. Arts (Mass. Institute Tech- nol.), Meeting 310, p. 50-56. " The Formative Force of Organisms," Science, vi., 4-6 (18S5). " Researches on Growth and Death and Biological Problems," Proc. Amer, Assoc. Adv. Sci. for 1S84, 517-521. "The Physical Basis of Heredity," Science, viii., 125-130 (1886). ^"Senescence and Rejuvenation," first paper, "On the Weight of Guinea- Pigs," Journ. of Physiol.^ xii., 97-153, pis. I. -III. (1891). INTRODUCTORY LETTER TO SENATOR M0S50 xv In 1890, in an address^ delivered before the Section of Biology of the American Association for the Advancement of Science, at the Indianapolis meet- ing, I first presented the view that there is a distinct correlation between the amount of protoplasm and the rate of growth, as determined by the experiments just referred to. In an article ~ entitled "Ueber die Vererbung und die Verjiingung," which has been translated and republished in the Ame7'-ican Natiir- alist, certain other general aspects of the quantitative study of protoplasm are dealt with. Finally, part of the conclusions developed were embodied in the "Middleton Goldsmith Lecture,"^ before the New York Pathological Society, in March, 1901. May I explain my point of view a little more fully ? The proper object, the final purpose, of biology is the discovery of the nature of life. The existence, or non-existence, of a vital force is a problem concerning which a great many dogmatic assertions have been put forth. It is evident, however, that all opinions as to the essential nature of vitality, however much they have differed otherwise, are pretty much alike in lackingf both scientific foundation and intellectual value. The agnostic position is the only possible 1 " On Certain Phenomena of Growing Old," Proc. Anier. Assoc. Adv. Science, xxix. "^ " Ueber die Vererbung und Verjungung," Biol. Centralbl., xv., 571-587. Transl." " On Heredity and Rejuvenation," American A^aturalist, xxx, i-g ; S9-101. 2 "The Embryological Basis of Pathology," Science, N. S., xiii., 481-498 ; alsp BQ?tgn M(d. Siir. Journal, cxliv., 295-305. xvi INTRODUCTORY LETTER TO SENATOR MOSSO and defensible one for a scientific man to occupy, who is loyal to the spirit of research. We may then assume with little risk of mistake that no hypothesis of life yet offered requires serious scientific consider- ation. A confession of agnosticism is here a positive contribution to the truth. On the other hand, there is no reason for giving up the endeavour to get nearer to the final goal of biology because attempts to reach it by the short cut of speculation have always failed. Indeed, at the present time much work is being done towards answering general questions, the answers to which appear necessary preliminaries to attacking the problem of life itself. Before the American Association for the Advance- ment of Science, in 1879, I read a paper " On Condi- tions to be Filled by a Theory of Life," which was published in abstract only.^ It contained an enumera- tion, as complete and exact as I could make it, of phenomena which any tenable hypothesis of vitality must explain ; the effort being made to generalise the statements to the farthest legitimate scientific limit, thus reducing as far as possible the number of phe- nomena. The result was a very vivid impression on my mind of the inadequacy of all hypotheses of vitality, and that impression is to-day undisturbed. Had circumstances permitted I should have devoted myself entirely to the study of general problems, but necessity early led me into teaching embryology, and in the acquisition of even my partial mastery of that > This abstract is reprinted as Appendix V to this volume. INTRODUCTORY LETTER TO SENATOR M0550 xvii intricate science so much time was absorbed, that I was forced to giv'e up the hope with which I started out, and have only the present book to offer as a fragment towards the fulfilment of the original plan of researches upon general biological phenomena. If one starts with the purpose of getting nearer a solution of the final problem of life, it is not difficult to devise numerous researches which would be likely to gain for us insight into the fundamental phenomena of biology. It was from the indicated standpoint that it seemed to me that one of the most promising opportunities for attack was offered by the changes which aofe effects in oro-anisms. These chang^es had been then, and indeed have been since, very little studied in a systematic way or from any general standpoint. It is assuredly one of the most general phenomena in the life history of organisms that they become old. From the ao^e of zero at the moment of sexual impregnation, animals and plants, broadly speaking, both pass through a series of changes until, barring accidents, they reach their limit of life ; by which we mean the maximum longevity achieved by each individual under the optimum of conditions. Organisms are created young and grow old, and the old produce young successors. Senescence is a pro- blem, of living matter, and, so far as known, has no parallel in non-living matter. It is an essential feature of life. It finds its most familiar expression in the gradual loss of the functional powers of the organ- ism, its end is death. My book is the outcome of an xviii INTRODUCTORY LETTER TO SENATOR MOSSO attempt to learn something as to the essential character and the cause of that loss. Age causes many progressive changes in the or- ganism, but none which are more obvious and more accessible to exact study than those of growth. Thus I was led to make my first experiments on growth. It soon appeared that the scope of the inquiry was expanding, and it has not been until now that the matters included have become sufficiently co-ordinated to justify their collective publication, — and yet the research remains fragmentary, narrow, and incom- plete. I can make no pretence of having solved the manifold problems of senescence, but I hope that you will at least find some of them more clearly formulated than hitherto, and also some real additions to our positive knowledge. For the purpose of studying growth as a function of age it was desirable to eliminate the influence of external conditions of a variable character as far as possible ; the readiest way to accomplish this was to choose a self-regulative organism ; accordingly one of the higher vertebrates was considered preferable, be- cause of all organisms they are the most independent of outside circumstances. It remained only to pick out a convenient species ; various considerations led to the choice of the guinea-pigs, Cavi'a cobaya. This animal offers the following advantages : it bears con- finement well, is robust and but little liable to disease, breeds readily, is easily managed and fed, and gentle when handled ; its maintenance is much less costly INTRODUCTORY LETTER TO SENATOR AdOSSOxix than that of a larger animal, an important considera- tion, as upwards of one hundred were kept at a time for several years/ Another important advantage de- pends on the fact that nearly every individual is marked with spots and blotches of brown and black differently from all others, so that they all can be readily told apart without any artificial marks, and hence it is easier to follow the growth of individuals. Occasionally there is one all white, but such white ones can be marked with spots of nitrate of silver on the hair. Guinea-pigs are so unintelligent that I have been unable to feel any interest except scientific in them, which perhaps also has been advantageous. Later, as recorded in Chapter III., a limited number of determinations of the weight of growing rabbits and chickens was also made. All these animals were kept in summer in suitable spacious pens in the country ; in winter, in large boxes in well lighted and ventilated rooms, warmed by artificial heat. They were carefully tended most of the time by myself ; the endeavour was to secure continuously the best hygienic conditions by unremit- ting attention ; it was my habit to make two visits daily. They were fed with the best food obtainable. To measure the growth the weights were taken of the growing and adult individuals, the weight being the only available measure for the whole animal,— and the only one permitting comparisons between ' During one winter upwards of eighteen barrels of carrots, three tons of hay, twenty-six bushels of oats, and some other food were eaten by my guinea-pigs. XX INTRODUCTORY LETTER TO SENATOR MOSSO different species of organisms. The weighings were made in the morning before the animals were fed. But they were kept always supplied with dry oats ; this practice is desirable because it helps essentially in preserving the animals in good condition. It does not entail a sufficient error in the weights to be ob- jectionable, because it is more or less constant and is not very large, as the animals will not eat a great deal of grain when they have plenty of other food. No fresh food was left in the pens or boxes over nieht. In all the weighings there is necessarily an error. A positive error, because the digestive tract, particu- larly the wide ccecum, contains always considerable quantities of undigested matter ; moreover, the blad- der may hold a greater or less quantity of urine. A negative error, because every illness, even a very slight indisposition, and every injury, such as a bite, for instance, causes a greater or less loss of weight. The quantitative values of these errors are presum- ably not very great ; they probably counterbalance one another to a certain extent in the averages, which may be accepted as approximately accurate. The advantage of these experiments over statistics taken from man lies especially in the fact that the same individuals are followed through the whole period of growth. Otherwise we may reach errone- ous conclusions ; thus in girls there is a very great acceleration of growth during the two or three years preceding puberty, that is, the epoch of the first men- INTRODUCTORY LETTER TO SENATOR MOSSO xx\ struation ; the acceleration shows itself also in a curve constructed from averages taken from a large number of observations upon many girls, but the variation appears less than it is for the individual and gives therefore an erroneous impression of the actual de- gree of prepubertal acceleration. This falsification necessarily ensues from the individual variations in the age of the first menstruation, — for the accelera- tions in one girl may occur at an older age than in another and a younger age than in a third, hence when a long series of observations is averaged the result shows an acceleration much longer in duration, but smaller in amount, than is characteristic for the in- dividual. Thus Dr. B. A. Gould found that the stature of American soldiers increased steadily up to thirty-five years to 1.7391 metres, which was the maximum average height for any age. This observa- tion does not prove that the growth period for Americans extends to thirty-five years, for the result noted may be due to more vigorous men growing more and surviving (but not growing) more years than the smaller and weaker men. The averag-e at thirty-five is greater than at thirty because — if the suggested explanation is correct — the shorter men have died off. This might be decided by statistical study of the relation of the ages at death from dis- ease to stature. It would certainly be worth while to investigate the problem, with a view of ascertain- ing whether there is any correspondence between the length of life and the size of individuals. A positive ^x\\ INTRODUCTORY LETTER TO SENATOR MOSSO answer to the Inquiry is to be expected. To return : — we have seen that if we do not compare the same individuals with one another we cannot be sure of correctly measuring the phases of growth. As guinea- pigs nearly complete their growth in one year, it was possible to make the requisite number of observations within a reasonable period, which Is not the case with man. In regard to my studies on the structure of cells in relation to growth, nothing special as to methods is to be said, as I have employed only the well-known standard procedures of histologists and embryol- oglsts. If the conclusions formulated In this book con- cerning cytomorphosis, senescence, and rejuvenation are correct, they will have direct bearing on many lines of investigation concerning growth, reproduc- tion, regeneration, degeneration, and pathological changes. If the conclusions are correct they will open, I hope, the way to many new interpretations. But I must stop. Let me, however, close this lengthy letter with the request that you accept the dedication of this volume as a memento of our long friendship, and as an expression of my admiration and attachment. Yours faithfully, Charles Sedgwick Minot. Harvard Medical School, Boston, Massachusktts, Jan. 13, 1908. The Problem of Age, Growth, and Death PROBLEM OF AGE, GROWTH AND DEATH THE CONDITION OF OLD AGE THE subject of age has ever been one which has attracted human thought. It leads us so near to the great mysteries that all thinkers have contem- plated it, and many are the writers who from the literary point of view have presented us, sometimes with profound thought, often with beautiful images connected with the change from youth to old age. We need but to think of two books familiar more or less to us all — that ancient classic, Cicero's De Senec- tute, the great book on age, one might almost say, from the literary standpoint, and that of our own fellow-citizen, my former teacher and professor at the Medical School, Dr. Holmes, who in his delightful Autocrat offers to us some of his charming specula- tions upon age. From the time of Cicero to the time of Holmes numerous authors have written on old age, yet among them all we shall scarcely find any 2 AGE, GROWTH, AND DEATH one who had title to be considered as a scientific writer upon the subject. Longevity is indeed a strange and difficult problem. Many of you doubt- less have had your attention directed recently to the republished translation of Cornaro's famous work^ and know how sensible that is, and as you read it you must have perceived how little in the practical aspect of the matter we have passed beyond the advice which old Cornaro gave to us, and yet silently in the medical laboratories, and in the physiological and anatomical institutes of various universities, we have been gathering more accurate information as to what is the condition of persons who are very old.'^ We know, first of all, from our common observation, that the very old grow shorter in stature. We see that they are not so tall as in the prime of life. The fig- ures which have been compiled upon this subject are instructive, for they show that at the age of some thirty years the average height of men — these figures refer to Germans — is 1 74 centimetres. It remains at that, however, only for a short period ; then it decreases ' Luigi Cornaro's work was originally published at Padua in 1558 under the title of Traitato de la vita sobria, English editions have been issued by George Herbert, by an anonymous editor (London, 1768), and G. H. Evans (1836), all which included other "discourses." The translation alluded to in the text was issued at Milwaukee in 1903 by Wm. F. Butler, and in the same volume the reader will find more apposite matter, Cornaro was born in 1464 and died in 1566. " He resigned his last breath without any agony, sitting in an elbow chair, being above an hundred years old." ^ Addison, in the Spectator (Oct. 13, 1711), wrote of Cornaro and thus com- mends him : " The ' Treatise' I mention has been taken notice of by several v-minent authors, and is written with such a spirit of cheerfulness, religion, and good sense, as are the natural concomitants of temperance and sobriety." Fig. I. Two Human Vertebral Columns in Section. A, female of about 35 years. B, male of 83 years (an extreme case of senile fusion and flexure of the vertebrae). 3 4 AGE, GROWTH, AND DEATH and at forty it is already less ; at fifty decidedly less ; and at sixty the change has become more marked ; un- til at seventy years v/e find that the height has shrunk from 174 to 161. There it remains, or thereabouts, through the remainder of life, though there may be a small further diminution. This decrease in stature is due largely to the changes in the vertebral column. First of all there is a stoop. The vertebral column is, to be sure, never straight, but in old age it be- comes more curved, and the result is a falling of the total stature. But this is not the chief cause, for in addition to this the softer cartilages and elements of the spinal column become harder, change into bone, and as that change occurs they acquire a less extent and become smaller, and the result is that the verte- bral column as a whole collapses somewhat and thus increases the diminution of height. We find, as we look at the old, a great change to have come over the face. The roundness of youth has departed ; the cheeks are sunken ; the eyes have fallen far back ; the lips are drawn in. All of these changes indicate to us, when we think upon them, the fact that there has been a certain shrinkage and shrivelling of that which is within and beneath the skin. Expressed in technical terms, we should call this an atrophy, and to anatomists the mere sight of the face of a very old person. Fig. 2, reveals at once this fundamental fact of an atrophy of the parts, an actual loss of some of their bulk, which is one of the most characteristic and fundamental marks of old THE CONDITION OF OLD AGE 5 age. The gait becomes shuffling, the foot is no longer Hfted free from the ground, as the old man walks along. He does not rise upon his toes, but the sole of the foot is kept nearly fiat and as he drags it cumbrously forward it is apt to strike upon the sidewalk. This indicates to the physiologist a less- ened power in the muscles, a lessened control over the action of these muscles, an inferior co-ordination of the movements, so that there has been in the old man, judged by his gait alone, a physiological deteri- oration as well as an anatomical atrophy. We notice too his slow speech, often difficult hearing, and im- perfect sight. All of these qualities show a loss, and we commonly think of the old as those who have lost most, who have passed beyond the maximum of development and are now upon the path of decline, going down ever more rapidly. One of the chief objects at which I shall aim in this course of lectures will be to explain to you that that notion is erroneous, and that the period of old age, so far from being the chief period of decline, is in reality essentially the period in which the actual decline going on in each of us will be least. Old age is the period of slowest decline — a strange, paradoxical statement, but one which I hope to jus- tify fully by the facts I shall present to you in this course. In the old person you note that there is in the mind some failure and also loss of memory — less mental activity, greater difficulty in grasping new Fk;. 2. Photograph of Chevreul, taken on his one hundredth birthday. He was asked to write in an album and replied : " Que voulez vous : que j'ecrive sur votre album ? Je vais ecrire mon premier principe philosophique, ce n'est par moi, quil'ai formule, c'est Malebranche — 'On doit tendre avec effort k I'infallibilite, sans y pretendre.' " Chevreul was born Aug. 31, 1786, and died Aug. 9, 1889. For the privilege of using this portrait I am indebted to Dr. Henry P. Bowditch, to whom the interesting original belongs. 6 Fig. 3. Photograph from a Child at Birth. The photograph is owned by Dr. H. P. Bowditch, by whose courtesy the present reproduction is published. (C) Adult, thirty years, very much reduced from life. Fig. 4. Ribs and Siernum, to show the progressive ossihcation of the carti- lage, which is indicated by stippling. — From specimens in the Warren Museum of the Harvard Medical School. lo AGE, GROWTH, AND DEATH thoughts, assimilating new ideas, and in adapting him- self to unaccustomed situations. All this betokens again the characteristic loss of the old. And as we turn now from these outward investigations to those which the anatomist opens up to us, we learn that in the interior of the body, and in every organ thereof, the species of change which I have referred to as characteristic of the very old is going on and has be- come in each part well marked.^ Let us first examine the skeleton. In youth many parts of the skeleton are soft and flexible, like the gristles and cartilages which join the ribs to the breastbone, but in the old man these are largely replaced by bone. Bone repre- sents an advance in organisation, in structure, as we say, over the cartilage. The old man has in that respect progressed beyond the youthful stage ; but that progress represents not a favourable change ; the alteration in structure from elastic cartilage to rigid bone is physiologically disadvantageous, so that though the man has progressed in the organisation or anatomy of his body, he has really thereby rather lost than gained ground. Indeed in the skeleton this principle of loss is already revealing itself.^ In the interior of the bones of the arms, of the legs, we find ' Especially valuable are the data concerning men and women of over eighty years collated by Sir George M. Humphry, in his book, Old Age, published at Cambridge (England) by Macmillan & Bowles in 1889. ^ The senile alterations in the jaw of man have been studied by Josef Kieffer, (" Beitrage zur Kenntniss der Veranderungen am Unterkiefer und Kiefergelenk des Menschen durch Alter und Zahnverlust," Zeitschr, fiir Morphol. u. An- thropol., xi, 1-82, Taf. i-iv, 1907). An important paper, offering good illus- trations of the general principles described in the course of the present lecture. Ill THE CONDITION OF OLD AGE n a spongy structure, bits of bone bound together in many different directions, as are the spicules or fibres in a sponge, and by being bound so together they unite hghtness with strength. As you know, a col- umn of metal, if hollow, is stronger than the same amount of metal in the form of a rod. So with the bones. If they have this spongy structure, if their interiors are full of little cavities with intervening spicules acting as braces in every direction, then they acquire great strength with little material (Fig. 5). Now in the old much of the internal spongy structure is dissolved away and there is left (Fig. 6) barely more than an external shell. Partly on this condition depends the greater liability of the bones in the old person to break. If we examine the muscles we see that they have become less in volume, and when we apply the microscope to them we see that the single fibres on which the strength of the muscles depends have become smaller in size and fewer in number.^ Professor B. Morpurgo ^ by an ingenious experiment has demonstrated that exercise increases the size of the muscles by increasing the size of the single fibres. |, Exercise produces a true physiological hypertrophy '' but no increase in the number of the fibres. This important discovery suggests the idea that senile muscular diminution is due chiefly if not exclusively ' This statement is the one currently accepted — but I have found, as yet, no exact investigation upon the relative size and number of the muscle fibres in old persons. ^ B. Morpurgo, " Ueber Activitats-hypertrophie der wilkiirlichen Muskeln," Virchows Arch. Pathol., Bd. cl., 522-554 (1897). Fig. 5. Section of the Head of the Thigh Bone of a Man of Thirty- seven Years. — Compare Fig. 6. '*?!? **:' '.^2*^ *'!^'^' Fig. 6. Section of the Head of the Thigh Bone of a Woman of Eighty-two Years. — Compare with Fig. 5, and note the loss of the spongy bone in the older femur. 13 14 AGE, GROWTH, AND DEATH to the reduction in size of the single fibres. The muscle has actually lost ; it is inferior, physiologic- ally speaking, to what it was before. You remem- ber how melancholy Jacques reminded us of this fact in speaking of the hose "a world too wide for his shrunk shank." His saying is justified by the loss of the muscles in volume and strength. The same phe- nomenon of atrophy shows itself in the digestive organs. Those minute structures in the wall of the stomach by which the digestive juice is produced undergo a partial atrophy, in consequence of which they are less able to act ; they are not so well organ- ised, therefore not so efficient as in earlier stages. The lungfs become stiffened ; the walls which divide off an air cavity from the neighbouring air cavities do not remain so thin as in youth, but become thick- ened and hardened, and the vital capacity of the lungs, that is to say the capacity of the lungs to take in and hold air, is by so much lessened. The heart — [it seems curious at first — is in the old always en- larged; but this does not represent a gain in real power. On the contrary, if we study carefully the condition of the circulation of the blood in the old, we find that the walls of the large blood-vessels which carry the blood from the heart and distribute it over all parts of the body — vessels which we call arteries — have lost the elastic quality which is proper to them and by which they respond favourably to the pumping action of the heart. Instead they have be- come hard and stiff. We call this by a Greek term THE COXDITIOX OF OLD AGE 15 for hardeninof, sclerosis, and arterial sclerosis is one of the most marked and striking characteristics of old persons. Now when the arteries become thus stiffened, it requires a greater force and greater effort of the heart to drive the blood through them, and in response to this new necessity, the heart becomes enlarged in an effort of the organism to adapt itself to the new unfavourable condition of the circulation established by age. But the power of the heart be- comes inferior along with the hypertrophy or enlarge- ment of the organ and we see that in the old, in order to make up for the feebleness of the enlarged heart, it beats more frequently. In other words, the pulse rate in the old person increases.^ We lind, for instance, that at the time of birth the pulse is at the rate of 134 beats to a minute. It rises slightly during ' My friend. Professor W. T. Porter, has had the kindness to compile the accompanying table for me. showing the pulse frequency from one to eighty years. For the first two months after birth the rate is about 130, after the third month, 140. The fcEtal rate is 135 to 140. . Mean . Mean . !Mean ° Frequency ° Frequency ° Frequency 0- 1 134 13-14 87 25-30 72 1- 2 Ill 14-15 - ... 82 30-35 70 2-3 108 15-16 83 35-40 72 3-4 loS 16-17 So 40-45 72 4-5 103 17-18 76 45-50 72 5-6 gS 18-19 77 5C^55 72 6- 7 93 19-20 74 55-60 75 7- 8 94 20-21 71 60-65 73 8-9 89 21-22 71 65-70 75 9-10 91 22-23 70 70-75 75 TO-II 87 23-24 71 75-SO 72 I [-12 89 24-25 72 80 and over 79 12-13 88 1 6 AGE, GROWTH, AND DEATH the first three months of infancy until at the end of the third month it reaches some 140 beats a minute; it soon falls off, however, and at the end of the first year it has sunk to 1 1 1 ; at five or six years it be- comes 98, and at twenty-one years it has sunk to 71 or 72. There are thereafter certain minor fluctua- tions in the rate of the heart-beat with advancing age, but generally it may be said that this value of 72 beats a minute is characteristic of adult life. But when a person becomes eighty years old, it has been found that upon the average the rate of the heart- beat rises and becomes 79 a minute. Hence it is clear that though the heart is larger, it has to make a greater effort, that is to say a more frequent beat, in order to maintain the necessary circulation of the blood. Another illustration. We can demonstrate by going back to the anatomical examination of the body, that those important structures which we call the germ cells, upon which the propagation of the race depends, and which present under the microscope certain clearly recognised characteristics by which they can be distinguished from all other cells of the body, — that these germ cells cease their activity alto- gether in the very old, and one of the great functions of life is thus blotted out altogether from the history of the individual. Turning now to the yet nobler organs, especially the brain, we see a curious change going on, a change of which old age presents to us the culminating re- THE CONDITION OF OLD AGE 17 cord. In order to study the weight of the brain, it is necessary to compare people of the same size, for the size and weight of the brain depend somewhat upon the size of the individual. Now it has been discov- ered by careful examination of persons of similar size that the brain begins relatively early to diminish its weight. Thus in persons of a height of 175 centi- metres, and over, of the male sex, it is found that in the period from twenty to forty years the brain weight is 1409 grams. But from forty-one to seventy years it has sunk to 1363, and in persons of from seventy-one to ninety it has shrunk to 1330. Women of equal size are not usual, and a more average height for women is 165 centimetres; a woman of such a height is likely to have — among the white races, be it understood — at twenty to forty years a brain of 1265 grams, at forty to seventy years of 1200 and at seventy-one to ninety years of only 1 166 grams.^ I give these figures because they show that there is no guessing, but a definite, positive knowledge, proving that soon after the maturity of life in the individual is reached, the shrinkage of the brain ' Ernst Handmann has recently published statistics on the growth of brain, based on measurements at the Leipzig Pathological Institute. See Archiv f, Anat. u. Entwickelungsges., 1906, p. i. The following summarises his results : Brain Weight in Grams Age Male Female 4- 6 1215 iig4 7-14 1376 1229 15-49 1372 1249 50-84(89) 1332 1196 1 8 AGE, GROWTH, AND DEATH begins, and then continues almost steadily to the very end of life.^ It is not only the anatomist, but it is perhaps almost equally the physiologist who gives us insight into the changes which go on in the old. I spoke a few mo- ments ago of the pulse rate, and of the change which that offers. At first sight it seems as if a greater pulse rate indicated an improvement, but if you recall the explanation given, you must acknowledge that this is by no means an acceptable interpretation, but that on the contrary the change is a clear mark of enfeeblement. In the respiration, also, we observe a like change. Here the comparison is not quite so easy as we should at first imagine, because there is a relation between the size of the individual and the respiration. The respiration, as you all know, frees the body from the products of combustion, particu- larly from that product which we know as carbon dioxide. The result of the combustion going on in the body (which in one of its end terms appears to us as carbon dioxide expelled from the lungs) is to pro- duce heat, to develop the necessary warmth for the maintenance of the proper temperature of the body. Now in the very young the bulk of the body is not great, but the loss of heat is very great, and this per- haps can be most readily explained to you if you imagine that you hold in one hand a very small • For further details the reader is referred to the invaluable work by Professor H. H. Donaldson of the Wistar Institute, The Growth of the Brain. A Study of the Nervous Systej?t in delation to Education, l2mo, London, 1895 (Walter Scott). THE CONDITION OF OLD AGE 19 potato and In the other a very large potato, both of which have come at the same moment from the same oven, and that you have just started out for a cold winter drive. You all know, of course, that in a little while the small potato, though it was as hot as the large one at first, will have lost its heat, will no longer serve to keep the hand warm, but the other hand, in which the bulkier potato is held, in which the volume of the heat — we might so express it, perhaps — is cor- respondingly great, benefits by the retained heat a long time. Essentially similar to this is the difference between the child and the adult. The child loses heat with comparatively great rapidity — the old per- son at a comparatively slow rate. Hence it is neces- sary for the child to produce more warmth in order to keep up the natural normal temperature of the body. When, therefore, we find that in the old person the respiration is diminished, and that the production of carbon dioxide from the lungs is greatly lessened, we are not. immediately to jump at the conclusion that the quality of physiological action has been debased — that we see here a sign of decrepitude. On the con- trary, the change is the result of physiological adapta- tion, of suiting the performance of the body to its needs. This is one of the great wonders, one of the mysteries of life, of which we here have a sample, the constant adaptation of the means to the end. That which the body needs is done by the body. A child needs more warmth, and its body produces more ; the old person needs less warmth, and his 20 AGE, GROWTH, AND DEATH body produces less. How this is accomplished we are unable to say, but constantly we see evidence of this purposeful accommodation on the part of the body — what is called by the physiologists the teleo- logical principle, the adaptation of the reaction of the body to its needs. There are innumerable illus- trations of this, many of which are of course perfectly familiar to us, although perhaps we do not think of them as illustrations of this great law of nature ; as, for instance, when we eat a meal, and the presence of food in the stomach calls into action the glands in the wall of the stomach by which the digestive juice is secreted. The juice is produced exactly at the time when it is needed. Innumerable, indeed, are the illustrations of this fundamental principle. There is another class of phenomena characteristic of the very old which will perhaps seem a little sur- prising to you after the general tenor of my previous remarks. I refer to the power of repair. This, modern surgery especially has enabled us to recog- nise as being far greater in the old than we were wont to assume ; and we know that there is a certain luxury, a certain excess reserve in the power of re- pair, and that we may go far beyond the ordinary necessities of our life in our demands upon our or- ganism, and still find that our body is capable of making the necessary response.^ Ordinarily the ' A most valuable and suggestive study of the excess supply of physiological resources has been made by Dr. S. J. Meltzer, " The Factors of Safety in Animal Structure and Animal Economy," Jotirnal Avier. Med. Assoc, vol. xlviii, pp. 655-664. THE CONDITION OF OLD AGE 21 amount of blood which we require is moderate in amount — moderate in the sense that the destruction of the blood continually going- on in the body is not a very rapid process ; but if, through some accident, a person loses a large quantity of blood, then, by one of these teleological reactions of which I have spoken, the production of new blood is increased, the loss is soon made up, and we discover that the blood, so to speak, has been repaired. Or when a little of the skin is lost, it quickly heals over. That again is due to the power of repair. Ordinarily so long as the skin remains whole that power is not called into ac- tion, but if a wound comes, then the regenerative force resident always in the skin, but inactive, comes into play and produces the mending which is such a comfort. So in old people, some of this luxury of reparative power persists, so that they can recover from wounds in a far better way than we should imagine if we judged them only by the general phys- iological and anatomical decline exhibited through- out all parts of the body. Some of the luxury of repair comes in usefully in old age. Now if we consider all these changes in the most general manner, we perceive that they are clearly of one general character ; they imply an alteration in the anatomical condition of the parts ; but it is an alteration which does not differ fundamentally in kind from the alterations which have gone on before, but it does differ in the extent and in part in the degree to which these alterations have taken place. When 2 2 AGE, GROWTH, AND DEATH the elastic cartilaginous rib becomes bony, nothing different is happening from that which happened be- fore, for there was a stage of development when the entire rib consisted of cartilage, and in the progress of development toward the adult condition that carti- lage was changed gradually into bone, thus producing the characteristic, normal, efficient bony rib of the adult. When old age intervenes, the change of the cartilage into bone goes yet further, but it progresses in such a way that it is no longer favourable, but unfavourable. We have then in this case a clear illustration of a principle of change in the very old which is, I take it, perhaps sufficiently well expressed by saying that the change which is natural in the younger stage is in the old carried to excess. But there is, in addition to this, something more, of which I have already spoken, namely the atrophy of parts, ' and by atrophy we mean the diminution, the lessening of the volume of the part. There is a partial atrophy of the brain in consequence of which that organ becomes smaller ; there is an extensive atrophy of the muscles in consequence of which their volume is diminished, and their efficiency decreased. Atrophy is pre-em- inently characteristic of the very old, and we see in very old persons that it becomes each year more and more pronounced. Indeed, it has been said recently by Professor Metchnikoff, a distinguished Russian zoologist, now connected with the Pasteur Institute in Paris, some of whose publications many of you have doubtless read, that his conception of THE CONDITION OF OLD AGE 23 the nature of senility, of old age, could best be ex- pressed in a single word, atrophy. " On resume la senilite par un seul mot: atrophie."^ That is his estimate of old age. But that is not the only es- timate of old age which has been made up to the present time. We find one, which is much more prevalent, is that which connects it with the condition of the arteries. Indeed, Professor Osier has written this sentence : " Longevity is a vascular question, and has been well expressed in the axiom that a man is only as old as his arteries." ^ Now these are medical views, not biological, and you will find that there is a very extensive literature dealing with old age in man based upon the conception that old age is a kind of disease, a chronic disease, an incurable disease. Medi- cal writers have put forward various conceptions giv- ing a medical interpretation of this disease. That to which I just referred is the favourite one, the one you are most likely to hear from physicians to-day — namely, the theory of arterial sclerosis, that the hard- ening of the walls of the arteries is the primary thing ; it interferes with the circulation, the bad circulation interferes with the proper working of every part of the body, and as the circulation becomes impeded, various accessory results are produced in the body in consequence. The body is brought to a lower or more diseased condition than before. Hence many medical writers interpret sclerosis of the arteries as * L'Ann/e biologique, Tome III., p. 256, 1897. ' W, Osier, The Principles and Practice of Medicine, i8g2, p. 666. 24 AGE, GROWTH, AND DEATH the primary factor, because they can trace so many alterations in the old which resemble diseased altera- tions to the natural changes in the arteries by which they acquire hardened and inelastic walls, which pre- vent the proper response of the artery to the heart- beat, upon which the normal healthy circulation largely depends. Another interpretation, very curious and interest- ing, is that which has been recently offered by the same Professor Metchnikoff whom I have just men- tioned. He has written a book upon the Nature of Man, translated in 1903, and published in this country. It is an interesting book. It gives a most attractive picture, incidentally, of Metchnikoff him- self, a man of pleasantly optimistic temperament, but a man thoroughly imbued with the spirit which has so often been attributed to contemporary scientific men, of cold, intellectual regard towards everything, towards life, towards man, towards mystery. For him mysteries of all sorts have little interest. Those things which are mysterious are beyond the sphere of what can hold his attention. He must reside in the clear atmosphere of definite, positive fact. This mental bias is shown in his book. He reviews In a happy way various past systems of philosophy ; he describes various religions ; and he points out his reasons for thinking that all of these are insufficient, that there is no satisfaction to be derived from any of the ancient philosophies or from any of the great world religions. Nevertheless he is an optimist. He THE CONDITION OF OLD AGE 25 has noticed as a result of his meditations upon the arrangements within our bodies that we suffer very much from what he calls disharmonies, by which he means imperfect adaptations of structures within us to the performance of the body as a whole. He mentions various instances of such disharmonious parts. They do not seem to me quite so imposing as apparently they do to him, for many of his dis- harmonies are based upon the fact that we do not know that a certain structure or part has any useful role to play in the body. But I am inclined to sus- pect that in many cases it is only because we are ienorant ; the list of useless structures in the human body was a few years ago very long ; it has within recent years been greatly shortened, and we should learn from this experience a caution in regard to judging about these things, which, I think, Professor Metchnikoff has failed to exert duly in forming his opinions on these disharmonies. Now among the disharmonies which he recognises is that of the great size of the large intestine, which is of such a calibre that a considerable quantity of partially digested food can be retained in it at one time. When such food is retained in the intestine, it may undergo a process of fermentation. There are many sorts of fermenta- tion, and some of them produce chemical bodies which are injurious to the human organism. Bacteria, which will cause fermentation of this sort, do actually occur in the human intestine. Metchnikoff thinks that, as we grow old, this tendency to fermentation increases. 2 6 AGE, GROWTH, AND DEATH Now the bodies produced by fermentation, the chem- ical bodies, I mean, get into our system and poison us. The result of the poisoning is that the native capacities of the various tissues and organs of the body are lowered, as happens in a man " intoxicated." ^ All parts of a man may be poisoned, not necessarily always with alcohol, but with many other things as well, and such a poisoning Professor Metchnikoff assumes to result from intestinal fermentation. More- over, he has further observations, which lead him to the idea that certain cells go to work upon the poisoned parts and do further damage. The cells in question are minute microscopic structures, so small that we cannot at all see them with the naked eye, but which have a habit of feeding in the body upon the various parts thereof whenever they get a chance. Cells of this sort go by the scientific name of phagocytes, which is merely a Greek term for " eating cells." The phagocytes, for instance, devour i pigment in the hair, and in old persons the production ' • The "poison-theory" of old age and death has recently been adopted by Prof. T. H. Montgomery, Jr., who has written : "Perhaps the best substan- tiated view ... is that natural death of the individual results from self- poisoning. The waste products of metabolism, some of them toxic, accumulate in the tissues until there results a true intoxication of the latter. We may try to transcribe this into a little more definite physiological phrase : death follows on account of the insufficiency of the excretion process, therefore the limit of life is a matter of excretion " ( Transactions Texas Academy of Scietice, ix, PP- 77. 78)' The author gives no evidence to justify these assertions, and they are therefore hardly available for discussion. P. yg, Montgomery dissents from my views on differentiation, because I have failed to recognise " the underlying factor of senescence, which is insufficiency of the excretion process." The present volume aims to prove that the underlying factor of senescence is another than that assumed by Montgomery. THE CONDITION OF OLD AGE 27 of white hair has resuhed from the activity of phago- cytes which have eaten the pigment which should have remained in the hair and kept its colour.^ But the pigment of the hair is not the only thing they will attack ; they will make their aggressive inroads upon any part of the body ; and Professor Metchnikoff has advanced the theory that old age consists chiefly in the damage which is done by phagocytes to pois- oned parts of the body, the poisoning being due to the fermentation in the large intestine. Now it has been observed by some of the German investigators ^ of these matters that the presence of lactic acid inter- feres with this fermentative process as it goes on in the intestine. Lactic acid, as its name implies, is the characteristic acid which occurs in milk when it be- comes sour. An Italian investio-ator'^ tried drinking some sour milk with the idea of stopping the fermenta- tion in the intestine, and so putting an end to the dele- terious change, and he believes in the short time that he tried it that it did him good — quite, you see, in the way of a patent medicine.* Professor Metch- nikoff, on this basis, has recommended, in his book on the Nature of Man, the regular drinking of sour ' This interesting fact was discovered by Metchnikoff, Annales de I'lnslilut Pasteur, igoi, p. 865. ^ Compare Bienstock, Archiv filr Hygiene, xxxix., p. 390 (1902) ; also Tissier et Martelly, Annales de F Instittit Pasteur, 1902, p. 865. ^ Albert Rovighi, '* Die Aetherschwefelsauren im Ham und die Darminfec- tion," Zeitschr. fiir Physiol. Chemie, xvi., pp. 20-46 ; see especially p. 43. * Rovighi used " kephyr," a fermented milk, in his experiments. For the mode of preparation and for the use of " kephyr," see Fischer, Die netteren Arzneimitteln, Berlin, 1887, p. 169. 28 AGE, GROWTH, AND DEATH milk,^ in the hope apparently that it will postpone senility, and will leave us our powers in maturity long beyond that period when we at present reach the fulness of our vigour, and advance the period of time when the changes of the years put us out of court. He regards this as an optimistic substitute for the various forms of philosophy and religion which many millions of people have found helpful in life, and cer- tainly it is the cheapest substitute which has ever been seriously proposed. There is another writer who, though having a Ger- man name, is in reality a Russian, Professor Miihlmann.^ He has another theory in regard to the fundamental nature of senility. He takes such instances as that which I spoke of, of respiration in connection with the production of warmth in the child's body and in the body of the adult, and finds that the diminution of the surface in proportion to the bulk of the body is characteristic of the old, and he concludes that we be come old because we do not have proportionately sur- face enough left. His view implies, apparently, that if ' " It is plain, then, that the slow intoxications that weaken the resistance of the higher elements of the body may be arrested by the use of kephyr, or better still of soured milk" (Metchnikoff, Nature of Man, 1903, p. 255). "^ Miihlmann has published several papers on old age, which contain much valuable and original matter. The following may be specially cited : " Weitere Untersuchungen iiber die Veranderung der nervenzellen in verschie- denem Alter," Arch, mikrosk. Anat., Iviii., pp. 231-247 (1901). " Ueber die Veranderungen der Hirngefasse in verschiedenem Alter," Arch mikrosk. Anat., lix., pp. 258-269 (igoi). His general views are presented in his memoir, Ueber die Ursache des Alters, Wiesbaden, 1900, and in a short essay in the Biologisches Centralblatt, Bd, XXI, pp. 8x4-828. THE CONDITION OF OLD AGE 29 we could keep ourselves more or less of the stature of pygmies we should be healthier and better off. I confess these theories, and many others which I might enumerate to you, seem to me to be somewhat fan- tastic — odd rather than valuable. Yet they all spring from this one common feeling, which is, I believe, a sinister influence upon the thought of the day in regard to the problem of age — they spring from the medical conception that age is a kind of disease, and that the problem is to explain the condition as it exists in man. Now that is precisely what I protest against. What I hope to accomplish in these lectures is to build up gradually in your minds some acquaint- ance with the fundamental and essential changes which are characteristic of age and in regard to which we have been learning something during the last few years — I might almost say only within recent years — and by means of this exposition to give you a broader view and a juster interpretation of the problem. I hope, before I finish, to convince you that we are already able to establish certain significant generalisa- tions as to what is essential in the change from youth to old age, and that in consequence of these gen- eralisations, now possible to us, new problems present themselves to our minds, which we hope really to be able to solve, and that in the solving of them we shall gain a sort of knowledge, which is likely to be not only highly interesting to the scientific biologist, but also to prove, in the end, of great practical value. Surely we cannot hope to obtain any power over 30 AGE, GROWTH, AND DEATH age, any power over the changes which the years bring to each of us, unless we understand clearly, positively, and certainly, what these changes really are. I think you will learn, if you do me the honour to follow the lectures further, that the changes are indeed very different from what we should expect when we start out on a study of age, and that the contributions of science in this direction are novel and to some degree startling. We can begin to approach this broader view of our subject if we pass beyond the consideration of man. If we turn from man to the animals which we are most familiar with, the common domestic quadrupeds, we see that they undergo a series of changes not very dissimilar to those which man himself must pass through. An old horse, an old dog, an old cat, shows pretty much the same sort of decrepitudes which characterise old men. But when we pass farther down in the scale to the fishes, or even to a frog, we discover great differences. Do you think you could tell a frog when it is old by the way it walks — for it never walks — or a fish by the amount of hardening of the lungs, when it has none ? Yet the lack of lungs is characteristic of the fish. And what becomes of the theory of arterial sclerosis when we go still lower in the animal kingdom, towards its lowermost members, and find creatures which live and thrive and have lived and thriven for countless generations, yet have no arteries at all ? They, of course, do not grow old by any change of their arteries. But when THE CONDITION OF OLD AGE 31 we come to study these various animals more care- fully, we learn that in them the anatomical and phy- siological features which I have indicated to you in my description of the changes in the human being are paralleled, as it were, by similar changes ; but only by similar, not by identical, changes. If we examine the insects, for instance, we see that in an old insect there is a hardening of the outer crust of the body which serves as a shell and a skeleton at once. That hardening increases with the age of the individual. We can see in the insect a lessening development of the digestive tract, and we can see — it has been demonstrated with particular nicety — a degradation of the brain.^ Insects have a very small brain, but when a bumblebee, or a honeybee, grows old, as he does in a few weeks after he acquires his wings, we see that the brain actually becomes smaller, and not only that, but as I shall be able to demonstrate to you with the lantern in the next lecture, the elements which build up the brain have each of them become smaller and the diminu- tion in the size of the brain is due in part to the shrinkage of the single microscopic constituents. There is another point of resemblance. We find that when one of the better parts of the body under- goes an atrophy, it becomes not only smaller, but its place is to a certain extent taken by the inferior ' C. F. Hodge, "Changes in Ganglion-Cells from Birth to Senile Death. Observations on Man and Honeybee," Journal of Physiology, vol. xvii., pp. 129-134 (1894). 32 AGE, GROWTH, AND DEATH tissues — especially by those which we call comprehen- sively the connective tissues, which might perhaps be best described to a general audience as that which is the stuffing of the body and fills out all the gaps between the organs proper. In consequence of per- forming this general function, they are very properly called connective tissues, since they connect all the different organs and systems of organs in the body together. Now in every body there is a continual fighting of the parts. They battle together, they struggle, each one to get ahead, but the nobler organ, generally speaking, holds its own. There are early produced from the brain the fine bundles of fibres which we call the nerves, which run to the nose, to the tongue, and to the various parts of the body. When these appear all the parts of the body are very soft. Afterwards comes in the hard and, we should think, sturdy bone, but never, under normal conditions, does the bone grow where the nerve is. The nerve, soft and pulpy as it seems, resists abso- lutely the encroachment of the bone, and though the bone may grow elsewhere, and will grow elsewhere the moment it gets a free opportunity, it cannot beat the soft delicate nerve.^ Similarly we find that the substance which forms the liver is pulpy, very ' The nerve fibres of the olfactory membrane arise very early in the embryo and form numerous separate bundles. Later the bone arises between the bun- dles, for each of which a hole is left in the osseous tissue, so that the bone in the adult has a sieve-like structure, and hence is termed the cribriform plate. It oiTers a striking illustration of the inability of hard bone to disturb soft nerve fibres. THE CONDITION OF OLD AGE ^^^ delicate. Those of you who have seen fresh liver in the butcher's shop know what a flabby organ it is, and yet though it is surrounded by the elements of con- nective tissue, which with great zest and eagerness produce tough fibres, it never gives way to them. The connective tissue is held back by the soft liver and kept in place by it. The liver is, so to speak, a nobler organ than the connective tissue and holds sway ordinarily ; but in old age, when the nobler organs lose something of their power, then the con- nective tissue gets its chance, grows forward, and fills up the desired place, and acquires more and more a dominating position. We can see this process in the brain of man or the brain of the bee. That which is the nervous material proper, microscopic examination shows us to be diminished everywhere in the old bee and in the old man, and the tissue which supports it, which is of a coarser nature and cannot perform any of the nobler functions, fills up all the space thus left, so that the actual composi- tion of the brain is by this means changed. There is, you see, therefore, during the atrophy of the brain, not only a diminution of the organ as a whole, but there is the further degradation which consists in the yielding of the nobler to the baser part, if I may so express myself. That, you recognise, necessarily im- plies a loss of function. The brain cannot under senile conditions do the sort of fine and efficient work which it could do before. Now if we go on from in- sects to yet lower organisms, we see less and less 34 AGE, GROWTH, AND DEATH appearing of an advance in organisation, of correlated loss of parts, and when we get far enough down the scale, senescence becomes very vague. The change from youth to old age in a coral or in a sponge is at best an indefinite matter. I should like, did the length of the course permit, to enlarge greatly upon this aspect of the question, and explain to you how it is that as the organism rises higher and higher in the scale, old age becomes more and more marked, and in no animal is old age perhaps so marked, certainly in no animal is it more marked, than in ourselves. The human species stands at the top of the scale and it also suffers most from old age. We shall learn, I hope, more clearly later on in the course of these lectures, that this fact has a deeper significance, that the connection be- tween old age and advance in organisation, advance in anatomical structure, is indeed very close, and that they are related to one another somewhat in fashion of cause and effect ; just how far each is a cause and how far each is an effect it would perhaps be prema- ture to state very positively ; but I shall show you, I think in a convincing way, that the development of the anatomical quality, or in other words of what we call organic structure, is ^Ae fundamental thing in the investigation of the processes of life in relation to age. We can see it illustrated again very clearly indeed when we turn to the study of plant life, for plants also grow old. Take a leaf in the spring. It is soft as the bud opens. The young leaf is deli- THE CONDITION OF OLD AGE 35 cate. It has a considerable power of growth. It expands freely, and soon becomes a leaf of full size. Then comes the further change by which the leaf gets a firmer texture ; the production of anatomical quality in the leaf, so to speak, goes on through the summer, and the result of that advance in the an- atomical quality is that the delicate, youthful softness and activity of the leaf is stopped. It cannot grow any more ; it cannot function as a leaf properly any more. The development of its structure has gone too far and the leaf falls and is lost, and must be replaced by a new leaf the next year. When we examine the changes that go on in any flowering plant, we observe always that there is this production of structure, and then the decay, the end or death. At first structure comes as a helpful thing, increasing the usefulness of the part, and then it goes on too far and impairs the usefulness, and at last a stage is pro- duced in which no use is possible any longer — the thing is- worthless. It is cast away in the case of the plant life ; and this casting away of the useless is a thing not by any means confined to plants ; it occurs equally in ourselves all the time ; at every period of our life we have been getting through with some portion of our body; that portion acquired a certain organisation, it worked for us awhile, and then being done with it, we threw it away because it was dead. Very early in the history of every individual there was a production of blood, and then followed the destruction of some of the blood corpuscles and their 36 AGE, GROWTH, AND DEATH remains were used for various purposes. The pig- ment which is in the Hver comes from the destroyed blood corpuscles, and it is believed that the pigment which colours the hair is derived from the same source. The blood corpuscles contain a material which when chemically elaborated reappears as the deposit which imparts to the hairs their colouration. You, of course, are all familiar with the loss of hair. It occurs to everybody, but did you ever think that it means that the hair which has lived has died, and that that hair which was a part of you has been cast off ? That is what the loss of hair means to the bi- ologist — the death of a part and the throwing away of it, and it is typical of what is going on through the body all the time. It occurs in the intestines, where the elements which serve for purposes of digestion are continually dying and being cast off. The outer skin is constantly falling off and being renewed, and that which goes is dead. In every part of the body we can find something which is dying. Death is an accompaniment of development ; parts of us are passing off from the limbo of the living all the time, and the maintenance of the life of each individ- ual of us depends partially upon the continual death going on in minute fragments of our body here and there. Our next step in this course of lectures will carry us into the microscopic world, and with the aid of the lantern at the next lecture I shall hope to demon- strate to you a little of the microscopic structure of THE CONDITION OF OLD AGE 37 the body and of the general nature of the change which exhibits itself in the body from its earliest to its latest condition. With such knowledge in our minds, we shall be able next to study some of the laws of growth. We shall gain from our microscopic information a deeper insight into some of the se- crets of the changes which age produces in the human body. II CYTOMORPHOSIS I THE CELLULAR CHANGES OF AGE TADIESAND GENTLEMEN: I endeavoured 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 that anatomical condition 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 charac- ter 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 our explanation 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 cannot study, as we now know, the 38 THE CELLULAR CHANGES OF AGE 39 problem of age without including in it also the con- sideration of the problems of growth and the prob- lems 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 conclu- sion that we can with the microscope now recognise in the living parts of the body some of those charac- teristics which result in old ao^e. Old agre 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 some- thing 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 cannot be distinguished by the naked eye, although they can be readily demonstrated by the microscope.-^ These units have long been knov/n to naturalists by the name of cells. The discovery of the cellular constitution of livinof bodies marks one of the great epochs in science, and every teacher who has 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 ani- mals. The date of the latter discovery was 1839. We owe it to Theodor Schwann, whose name will ^ I have estimated the average diameter of the cells in the human adult as fifteen thousandths of a millimetre (0.015 mm.). One millimetre is approxi- mately one twenty-fifth of an inch. This estimate is probably not exact, but may serve to indicate the order of cell dimensions. ^ /c Fig. 7. Cells from the Mouth (Oral Epithelium) of the Sala- mander, to show the phases of cell division or mitosis. The cells are not represented in the living slate, but artificially preserved and coloured. In the living cell there is no such marked contrast of colour between the protoplasm and the nucleus as appears in these figures. — After Sobotta, 40 THE CELLULAR CHANGES OF AGE 41 therefore ever be honoured by all investigators of vital phenomena. What the atom has been to the chem- ist, the cell is to the naturalist, but with this differ- ence, atoms are hypothetical, cells are known by direct observation. Every cell consists of two essen- tial parts. There is an inner central kernel which is known by the technical name of nucleus, and a cov- ering- mass of livingr material which is termed the protoplas7n 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, exhibiting in this view no very distinctive characteristics, and therefore offering a somewhat marked contrast with the darker oval 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, chromatine, which owes its name to the very marked affinity which it displays for the various artificial colouring matters which are employed in microscopical re- search.^ The third of the internal nuclear constitu- ' It seems to me very doubtful whether the distinction drawn between the network and the chromatine of the nucleus is valid — but the distinction is usually affirmed in the text-books of to-day. There are observations whict 42 AGE, GROWTH, AND DEATH ents we may call the sap (hyaloplasma), 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 sepa- rate peculiarly elongated granules, each of which is termed a chromosome. The chromosomes are very conspicuous under the microscope, because they ab- sorb artificial stains of many sorts with great avidity and stand out therefore conspicuously coloured in our microscopic preparations. They are much more conspicuous than is the substance of the resting nucleus. The fact that we can readily distinguish the dividing from the resting nucleus under the microscope, — compare Fig. 72, — we shall take advan- tage of later on, for it offers us a means of investigat- ing the rate of growth in various parts of the body. I should like, therefore, to emphasise the fact at the present time sufficiently to be sure that it will remain render it probable that there is in the network only one constituent of which the chromatine is a functional modification, varying in extent in accordance with the alternating phases of cell-life. THE CELLULAR CHANGES OF AGE 43 in your minds until the final 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 di- vision. 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 physio- logically. It has a certain individuality of its own. In many cases cells are found to be isolated or sepa- rated 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 re- lated, we speak of the union of cells as syncytium. Of this I offer you an illustration in the second picture upon the screen (Fig. 8), which represents the em- bryonic 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 exist- ence of fibrils, which are characteristic of connective tissue, and at the stage of development represented 44 AGE, GROWTH, AND DEATH 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 in- stance, 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. If we are to be scientifically exact we must note Fig. 8. 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, intercellular fibrils. that in the early stages of vertebrates, the germ or embryo is not constituted of discrete cells. There are nuclei, and each nucleus is surrounded by proto- plasm. Each nucleus is perfectly individualised, but its protoplasm merges into that about the neigh THE CELLULAR CHANGES OF AGE 45 bouring nuclei. All the primitive parts are then true syncytia. Thus it happens that in Fig. 9, which represents sections of a very young rabbit germ, the single cells are not marked off. Nevertheless it is customary and convenient to speak of the cells even at such a stage. The actual delimitation of the cells occurs in older stages in nearly every part of the body. The blood corpuscles are always the first cells in vertebrates to become definitely individualised. There, is, in fact, as you probably all know, a con- stant growth of cells ; and this growth implies also, naturally, their multiplication. There has been in each of us an immense number of successive cell generations, and at the present time a multiplication of cells is going on in every one of us. It never entirely ceases as long as life continues. The de- velopment 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 earliest 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. Some authorities use specification as a tech- nical synonym for differentiation. At first cells are alike ; In older Individuals the cells have become of different sorts, they have been differentiated Into 46 AGE, GROWTH, AND DEATH various classes. This whole phenomenon of cell change is comprehensively designated by the single i^-l'^ '^i^Si^^2S^I&' n ' "^ -ok/t^V- . , - ----- - :>:^ ,v -"^?'® SSi^feMsi^-*^^''^ i^^^ _~^ -'i-'-^-'--^^ ^^s^. Fig. 9. 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. word, cytomorphosis, which is derived from two Greek words meaning cell and foi^m, respectively. THE CELLULAR CHANGES OF AGE 47 A correct understanding of the conception cytomor- phosis is an indispensable preliminary to any com- prehension of the phenomena of development of animal or plant structure. I shall endeavour, there- fore, now to give you some insight into the phenomena of cytomorphosis as regarded by the scientific bio- logist. The first cells which are produced are those which form the young embryo. We speak of them on that account as embryonic cells, or cells of the embryonic type. Our next picture illustrates the actual character of such cells as seen with the micro- scope, 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 sec- • The layers are three in number, and are known as the ger?n-layers; the outer layer (uppermost in each of the three sections in Fig. 9) is the ectoderm. the middle the mesoderm, and the inner one the entodertn. The science of embryology has for its chief task to trace the numerous modifications and often very complicated metamorphoses which the three simple germ-layers pass through in order to produce the complex organs of the adult. Our present conceptions of the structure of multicellular animals are based on two great discoveries, first of the germ-layers, second of cells. 48 AGE, GROWTH, AND DEATH ^^■'-. €a-\ > tions 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 rabbits is found to be very similar ; and indeed if we should pick out one of these cells and place it by itself un- der 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 ^r"<^~^^^M^~^ZZA embryonic cells are all very much alike, simple in charac- ter, have relatively large nu- clei, and only a moderate amount of protoplasm for each nucleus to complete the cell. Very different is the con- dition of affairs which we find when we turn to the micro- scopic examination of the adult. Did time permit it corresponds to the inner surface ^q^M be pOSsiblc tO Study of the tube. . ^ , a succession ot stages and show you that the condition which we are about to study as existing actually in the adult is the result of a FiG. lo. Portion of a Transverse Section of the Spinal Cord of a Human Em- bryo OF Four Millimetres. Harvard Embryological Collec- tion, series 714. The spinal cord at this stage is a tubular struc- ture. The figure shows a por- tion of the wall of the tube ; the left-hand boundary of the figure THE CELLULAR CHANGES OF AGE 49 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 illus- trating various adult structures. The first is, how- ever, a part of a cross-section of the embryonic spinal cord in which you can see that much of the simple char- acter 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 appear- ance. 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 fibre by which motor impulses are conveyed from the spinal cord to the muscles of the body. The cell has numerous elongated branching processes stretching out in various directions, but all leading back towards the central body in which the nucleus is situated. These are the processes which serve to carry in the nervous impulses from the periphery towards the centre 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 fibre, and forms the axis, as it was formerly termed, or axon, as it is at present more 5° AGE, GROWTH, AND DEATH usually named, of the nerve fi- bre as we en- counter it in an ordinary nerve. This single thread-like prolong- ation of the nerve cell is likewise con- stituted by the liv- ing protoplasm and serves to carry the impulses away from the cell body and transmit them ul- timately to the mus- cle fibres which are to be stimulated to contraction. In the embryonic spinal cord none of these processes existed, and the amount of the protoplasm in the nerve cell was very much smaller. As development pro- gressed, not only did the protoplasm body grow, but the processes gradually grew out. Some of Fig. II. Copy of the Original Figure FROM THE Memoir of Deiters, in which the proof of the origin of the nerve fibres 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, Deii. Nu is the spherical nucleus with its charac- teristic central dot. THE CELLULAR CHANGES OF AGE 51 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^ shows us a section through the Fig. 12. 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 Kolliker. 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 organisa- tion by which they are adapted to serve as supports for the nervous elements proper. They play in the * The illustration referred to is not reproduced in the text. 52 AGE, GROWTH, AND DEATH 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 ap- pearances which this figure offers for our considera- tion can be recognised in any similar preparation of the embryonic cord. Obviously, then, from the em- bryonic 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 strik- ing 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 co-ordination of movements. These large cells occur only in this portion of the 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 illus- trates yet other peculiarities of the adult nerve cells. The upper figures in this plate are taken from cells which have been coloured uniformly of a very dark hue, in consequence of which they are rendered so opaque that the nucleus which they really contain is hidden from our view. But the deep artificial colour 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 rig.l. A;/ # 1^ ^ r^ (^ }' '^m v^ lill iit-^ F 1(1.3. Fiij.4. Fiff. J ..J FIG. 13. Various Kinds of Human Nerve Cells, as Described in the Text. — After Sobotta. 53 54 AGE, GROWTH, AND DEATH 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 bottorn figures represent the kind of nerve cells which occur upon the roots of the spinal nerves, and each of which is surrounded by a special protective envelope of small non-nervous cells. 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 tis- sues which are known by the technical name of epithe- lia. You can notice immediately in the figures on the plate (Fig. 14) 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 of the various figures now before you, of the further fact that these epithelia are unlike one another. The figures represent epi- thelium, 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. I'ic/.l. vjgiva^ -- ^grjBW', %.^. />y.j. /'V_^. 4 Fig. 14. Sections of Four Sorts of Epithelium, i, from the human ureter, X 450 diams.; 2, stratified ciliated epithelium from the respiratory region of the human nose, X 500 diams. ; 3, ciliated epithelium from the human ductus epididymidis, X 420 diams.; 4, surface view of the pigmented epithelium from the retina of a cat's eye, X 280 diams. — After Sobotta. 55 56 AGE, GROWTH, AND DEATH 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 ap- pearances. This lack of uniformity is due chiefly to the fact that the cells change their appearance accord- ing to their functional state. We can actually see in these cells under the microscope the material im- bedded in their protoplasmic bodies out of which the A B Fig. 15. To Show the Orbital Gland of a Dog. 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. 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 THE CELLULAR CHANGES OF AGE 57 large, and their protoplasmic bodies do not readily absorb certain of the staining matters which the microscopist is likely to apply to them (Fig. 15, A). 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 (Fig. 15, B), 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 cor- related with their functions. We can actually observe that the cells of the orbital, and, it might be added, 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 the orbital-gland cells from the simple stage of the embryonic cells. Something similar to this can be recognised in the next of our pictures representing sections 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 ac- cumulated 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 58 AGE, GROWTH, AND DEATH accumulated (Fig. i6, A^. When this raw material is turned 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 Fig. i6. 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. cells to again elaborate the material for secretion be- fore they can a second time become functionally active. Here we have something of the secret of the produc- tion of the various juices in the body revealed to us. Other excellent examples of the differentiated con- dition of the cells are afforded us by the examination THE CELLULAR CHANGES OF AGE 59 of hairs, of which I will show you two pictures. The Fig. 17. Section of the Human Skin, Made so that the Hairs are Cut Lengthwise. ^/, erector muscle of the hair ; ep, epidermis ; c, deep skin or dermis ; /J>, hair follicle ; J?p, root of hair ; J?c, subdermal tissue ; gls, sweat glands ; Cap, fibrous layer (aponeurosis). X 15 diameters. — After Sobotta. first represents a section through the human skin taken in such a way that the hairs are themselves cut 6o AGE, GROWTH, AND DEATH lengthwise and you see not only that each hair con- sists 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, Ap, 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 (Fig. i8), 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 inter- vening substance. The organs themselves consist of many separate parts which are also joined by a substance which keeps them in place. This sub- stance has received the appropriate name of connec- tive tissue. We find in the adult that it consists of a considerable number of structures. There are cells and fibres 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 sub- stance, 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 THE CELLULAR CHANGES OF AGE 6i of bone, where the substance Is made tougher and stronger by the deposit of calcareous material. No- ^ » * r"^ * # 5> ^_ \ **. w /.y Fig. i8. Cross Section of the Root of a Hair, hbl, longitudinal, hbr, circular fibres of the hair sheath ; bg, blood-vessels ; gl, hyaline sheath ; aiv, outer layer of follicle ; i^v, inner layer of follicle ; r, outer cuticle of the hair; 7, Huxley's layer of the follicle ; 2, Henle's layer of the follicle. X 3oo diame- ters. — After Sobotta. thino- like cartilao-e, nothino- like bone, exists in the 62 AGE, GROWTH, AND DEATH early state of the embryo. They represent something different and new. The next of our illustrations, Figs. 19 and ^o, show us muscle fibres of the sort which serve for our volun- tarymotions and are connected ty p ically with some part of the skele t o n . These mus- clehbresare elongated structures. Each fibre contains a contractile substance different from protoplasm, and which exists in the form of delicate fibrils which run lengthwise in the muscle fibres (Fig. 19), and is so disposed, further, that a series of fine lines are produced across the fibre itself (Fig. 20), each line cor- responding with a special sort of material different from the original protoplasm. These cross lines give to the voluntary Fig. 19. Cross Section OF A Lingual Muscle Fibre OF THE Mocassin Snake, An- CISTRODON PiSCIVORUS. The single large dark spot repre- sents a nucleus. Each small dot represents a cross section of a muscle fibril. There are several hundred in each fibre. ,1 Fig. 20. Part OF a Muscle Fibre of the Human Tongue to Show the Cross Stri- ations. Two nuclei are included, one of which is shown at the edge of the fibre, the other in surface view. In the adult striated muscle fibres of mam- mals the nuclei are su- perficially placed. THE CELLULAR CHANGES OF AGE 63 muscle fibres a very characteristic appearance, in consequence of which they are commonly desig- nated in scientific treatises by the term striated. A striated muscle fibre is that which is under the con- Blood-ves- sels. Nucleus. Nucleus. Inner sur- face of the retina (to- ward the light). Blood-vessels. Fig. 21. Section of a Human Retina, from Stohr'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 pig- ment 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. trol of our will. It should perhaps be mentioned that the muscle fibres of the heart are also striated, though they differ very much in other respects from the true voluntary muscles. Last of all for this series of demonstrations, I have 64 AGE, GROWTH, AND DEATH chosen a section of the retina (Fig. 21). One can see near the top of the figure the pecuHar cyhndrical and tapering projections (rods and cones) which are characteristic of a retina, projections which are of especial interest because they represent the apparatus by which the rays of Hght are transformed into an actual sensory perception. After this has been ac- complished, the perception is transmitted into the in- terior substance of the retina, and by the complication of the figure you may judge a little of the complica- tion of the arrangements by which the transmission through this sensory organ is achieved, until the perception is given off to a nerve fibre and carried to the brain. There is not time to analyse all I might present to you of our present knowledge concerning the structure of the retina. But it will, I think, suf- fice 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 what 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 phenome- non of life ; it is the central problem of all biological THE CELLULAR CHANGES OF AGE 65 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. Recent careful investigations have been made upon the rela- tion 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 ' G. Levi, " Vergleichende Untersuchungen ueber die Grosse der Zellen," Verhandl. Anat. Ges., xix., 156-158. G. Levi, " Studi sulla Grandezza delle ceWvile," A 7'ckivio ital. anat. embriol., v., pp. 291-358. This paper is important and suggestive. S 84.1x71.r> . Bo« laiirus Eqihi.s «-(iIhiI1iis 7L'. 4x50.7 07. 8 >',">( $-7 > r 7 ^4.f;.l) (D rviiocepliald.s iKibuin Feli:* domestic* 1 Lopij.«;riini('iilii.>? (l(Hii»vii«iis 60.7x50.3 ,^.aOx54.0 44..^.x30.4 r Mils nil Ills nlbus Mu.s iiiii.s(-iiiii.suii)ii.s Alcilaplia driftifi^a 37.«x:kV.7 3<-..fixL*2.J> .'Jl. 5x28.0 Fig. 22. Motor Nerve Cells of Various Mammals, all from the cervical region of the spinal cord. The cells are represented all uniformly magnified. The cross lines on each figure indicate the directions in which the original cells have been measured. — After Irving Hardesty. 66 THE CELLULAR CHANGES OF AGE 67 so called.^ This Is demonstrated by the slide now be- fore us (Fig. 22), which shows corresponding motor nerve cells from the spinal cords of twelve different mammals arranged in the order of their size — the ele- phant, the cow, the horse, man, the pig, the dog, the baboon, the cat, the rabbit, the rat, the mouse, and a small bat. You recognise immediately 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 calibre and length of the striated or voluntary muscle fibres. But with these exceptions our state- ment 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 advan- tage, and enables us to speak in general terms in regard to the growth of cells, and renders it superflu- ous 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 degen- eration of cells. For we find that, after the differ- entiation has been accomplished, there is a tendency ' Irving Hardesty, " Observations on the Medulla Spinalis of the Elephant, with Some Comparative Studies of the Intumescentia Cervicalis and the Neurones of the Columna Anterior," Journ. Co77ip. Neurol., xii, 125-182, pis. ix-xiii. 68 AGE, GROWTH, AND DEATH 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 con- sequence. Such cases of differentiation we speak of as a degeneration, and it may occur in a very great Fig. 23. Group of Five Nerve Cells FROM THE First Cervical Ganglion of a Child at Birth. Specimen preserved with osmic acid. X 500 diams. — After C. F. Hodge. 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 un- able to maintain itself in good physiological condition, and failing to keep up its own nourishment it under- goes a gradual shrinkage which we call atrophy. A very good illustration of this, and a most important THE CELLULAR CHANGES OF AGE 69 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 Fig, 24. Group of Four Nerve Cells from the First Cervical Ganglion of a Man Dying of Old Age at Ninety-two Years. Specimen preserved with osmic acid. C, C, two cells still intact, but loaded with pigment granules ; c, c, two cells which have disinte- grated. X 500 diams. — After C. F. Hodge. us, copied from investigations^ of Professor Hodge, of Clark University. The two figures represent human nerve cells taken from the root of a spinal ' C. F. Hodge, " Changes in Ganglion Cells from Birth to Senile Death," J our 7ial of Physiol.^ vol. xvii., pp. 129-134. 70 AGE, GROWTH, AND DEATH nerve. The first figure shows these cells as they exist in their first maturity ; the second figure, as they appear in a person of extreme old age. In the latter you will readily notice that the cells, C, have shrunk and no longer fill the spaces allotted to them, the nuclei have become small, and have lost their conspicuous granules, 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 differ- ent 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 second figure that the atrophy of the cells has led on to their disin- tegration (c, c), 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^ upon the screen show us the brain of the humblebee. 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. ' The two figures of the bee's brain are not reproduced in the text. THE CELLULAR CHANGES OF AGE 71 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 organisation so that their substance passes from a living to a dead state. No more perfect illustration of this sort of chang-e 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 lan- guage, horny substance. Ultimately the cell proto- plasm becomes nothing but horny substance and is absolutely dead. Here life and death play together and go hand in hand. Hence the term necrobiosis, death and life in one. Another form of deo^eneration 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 disin- tegration of these cells also ; and they break down and are lost. This form of degeneration is termed hyper- trophy, and represents a third type, as I have stated. 72 AGE, GROWTH, AND DEATH 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, namely the phase of the death and final re- moval of the cells. The degenerative change, when complete, 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 impor- tant method of the removal of cells is by a chemical process in consequence of which the cells are dis- solved 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 ' Two kinds of cells are commonly found in the saliva, the first are cornified cells sloughed off the lining epithelium of the mouth, the second are salivary- corpuscles, which are really white blood corpuscles (leucocytes) that have migrated into the saliva and died. Being dead they have enlarged themselves by the imbibition of water. THE CELLULAR CHANGES OF AGE 73 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 stom- ach. 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 investiga- tions 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 be 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 ^ This remarkable phenomenon is known by the name of autolysis. An ex- cellent general exposition of the subject has been made by Dr. P. A. Levene of the Rockefeller Institute in the Harvey Lectures, 19C5-6, p. 73. 74 AGE, GROWTH, AND DEATH 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 impor- tance. 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 role 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 prob- lem of the death of cells is concerned, not as in- dicating the cause of death, but as a phenomenon for the display of which the death of the cell offers an opportunity. A word of caution ! Let me state explicitly that the death of cells does not depend always upon their completing the cytomorphic cycle. Death may befall a young cell just as it may befall a young child. I think it probable in all such cases, 3 The best known case of fragmentation is that of the red-blood corpuscles. Vast numbers of them are constantly destroyed at the close of their cytomor- phosis by this process, which has been studied by numerous investigators chiefly in the spleen and the liver. Another noteworthy illustration of this method of cell destruction was discovered by Ranvier (" Des clasmatocytes," Archives V anatomie niicrosc, iii., 122-139) among wandering cells which occur in the connective tissue of mammals, THE CELLULAR CHANGES OF AGE 75 even when the death of the cells is normal and occurs in the regular course of development, that the cause of the cells' death is extraneous to them, not intrinsic. 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 permis- sible to depart from the strict theme which we have before us, and I will content myself, therefore, with throwing upon the screen two tables ^ which illustrate 1 I. Death of Cells First. Causes of death. A. External to the organism : (i) Physical (mechanical, chemical, thermal, etc.). (2) Parasites. B. Changes in intercellular substances (probably primarily due to cells) : (i) 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 : (i) Atrophy. (2) Disintegration and resorption. B. Indirect death of cells : (i) Necrobiosis (structural change precedes final death). (2) Hypertrophic degeneration (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. (i) Cytoplasmic changes : (a) Granulation. (b) Hyaline transformation. 76 AGE, GROWTH, AND DEATH 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, and which was subsequently published.^ If any of you should care to make a closer acquaintance with them they are therefore readily accessible to you. In order to render the nature of cytomorphosis clearer to you let me ask your attention for a concrete example, the biological history of the red blood cor- puscles, minute bodies, which in man are normally cup- shaped,^ as they are in various other mammals also. It {c) Imbibition. {d) Desiccation. {e) Clasmatosis. (2) Nuclear changes : {a) Karyorhexis. {b) Karyolysis. B. Hypertrophic degeneration. , (i) Cytoplasmic : {a) Granular. {b) Cornifying. {c) Hyaline. (2) Paraplasmic : (a) Fatty. {b) Pigmentary. {c) Mucoid. {d) Colloid, etc. (3) Nuclear (increase of chromatin). ' "The Embryological Basis of Pathology," the Middleton Goldsmith Lecture delivered before the New York Pathological Society, March 26, 1901, Science, xiii., 481-498, and Boston Med. Sur. Journal, cxliv., 295-305. It was in the course of this lecture that the law of cytomorphosis was first publicly announced and formulated. * The form usually ascribed to them is that of a biconcave disc, a shape which appears to be a post-mortem artefact. The true shape was first proven by THE CELLULAR CHANGES OF AGE 77 may interest you to know that it was not until 1902 that the actual shape was correctly recognised. The corpuscles are so small that about 5,000,000 occur in a cubic millimetre of blood. The picture now before us illustrates the life history of these cells. ^ In the earliest stage of their cytomorphosis the cells have each a well formed nucleus, Fig. 25, No. i, with a min- imal amount of protoplasm around it, indeed the pro- toplasmic envelope is so exceedingly thin that earlier observers thought the corpuscles began as naked nuclei without a cell body.^ In the next stage, No. 2, the cell body has grown so that there is more pro- toplasm than before in proportion to the volume of the nucleus. The cell body around the nucleus is at this time loading itself with haemoglobin, the red substance which plays, as you all know, so important a part In respiration. The enlargement of the cell soon reaches Weidenreich {Archiv f. mikrosk. Anat., LXI., p. 6i), whose observations have been confirmed in my laboratory, especially by Professor F. T. Lewis {Journ. Med. Research, x., 513, 1904). ' As regards the drawings in Figure 25, it should be stated that from each embryo a single corpuscle was selected by me as typical. In the specimens cor- puscles in many different stages of development are found together and the se- lection of a typical corpuscle is difficult. The choice is necessarily somewhat arbitrary. The drawings illustrate the progress of development correctly, except that the transition from the last nucleated stage. No. 6, to the final cup-shaped stage, No. 8, is still subject to discussion, but No. 7 was drawn from an actual corpuscle, which had certainly lost its nucleus and become smaller, and apparently was just beginning to assume the cup-shape. How the nucleus disappears is not known with certainty; there are two principal views, the first that the nucleus is extruded, the second that it is dissolved by the rest of the cell. The problem of the disappearance of the nucleus, though very important cytologically, is of secondary interest for the main purpose of the present lecture. ^ For example, F. M. Balfour, Works, vol. i., p. 50. 78 AGE, GROWTH, AND DEATH Its maximum, No. 3, and the corpuscle is in the Ichthyopsidan stage, ^ which means the stage which Fig. 25. Life History of Blood Corpuscles, Rabbit Embryos. No. I. Embryo of 8 days, 6 hours, No. 8S3. No. 2. Embryo of 9 days. No. 621. No. 3, Embryo of 9 days, 12 hours. No. 567. No. 4. Embryo of 10 days, No. 940. No. 5. Embryo of ir days. No. 556. No. 6. Embryo of 14 days, 18 hours. No. 143. No. 7. Embryo of 16 days, 12 hours, No. 1229. No. 8. Embryo of 18 days, No. 167. is permanent and the highest attained in fishes and amphibians. The next stage. No. 4, is characterised by a shrinkage of the nucleus, a degenerative change, but bringing the physiological advantage of more room for haemoglobin in the corpuscles. When the nucleus shrinks it loses the granular appearance it had before and also stains more deeply with the mi- croscopists' dyes, Nos. 5 and 6. This is called the Sauropsidan stage, ^ because it is that which is per- manent and the highest attained in reptiles and birds. * C. S. Minot, " Morphology of the Blood Corpuscles," Proc. Amer. Assoc, Adv. Science, xxxix. (1890), p. 341, and Anatomise ker Anzeiger, v., p. 601. THE CELLULAR CHANGES OF AGE 79 Next the nucleus disappears, No. 7, probably by being completely expelledt from the cell, and by further con- traction the enucleate cell assumes the cup-shape, thus evolving the true mammalian non-nucleated red corpuscle, No. 8. The cells have been differentiated and are now degenerating. The last stage of all is their death and removal.^ Their usual end is break- ing up into small fragments, which are then eaten by phagocytes and so disposed of. Sometimes, however, corpuscles are devoured whole by phagocytes. It is possible that corpuscles are normally destroyed by imbibing fluid until they burst, as is said to occur under pathological conditions. To recapitulate: i, the cells have little protoplasm ; 2, the protoplasm grows ; 3, differentiation occurs ; 4, degeneration; 5, disinte- gration of the cells ; 6, removal of their remains. Let us turn from the study of details and illustra- tions, to the examination of general considerations. Our first endeavour must be to answer the question : How, from the standpoint of cytomorphosis, ought we to look upon old age ? Cytomorphosis, the succes- sion of cellular changes which goes on in the body, is always progressive. It begins with the earliest de- velopment, continues through youth, is still perpetu- ally occurring at maturity and in old age. The r6le 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 con- ception is at all familiar to the members of this audi- ' Compare Weidenreich, Anaiotn. Anzeiger, xxiv., pp. 186-192. 8o AGE, GROWTH, AND DEATH ence. 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 em- bryo before any spinal column is formed an easily visible structural axis 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 almost disappeared, and its disappearance begins very early during embryonic life. There are numerous blood-vessels which we find to occur in the embyro, 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 for ever. 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 THE CELLULAR CHANGES OF AGE 8i called the middle-kidney, and which is the only renal organ found in the adult, for the head-kidney disap- pears in these animals long before the adult condition is reached. In the mammal there is yet a third kidney. We have during the embryonic stage of the mammal always a well-developed excretory organ which cor- responds 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 dis- solved 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. Many of the bony elements of the skeleton in the adult, in the embryo exist merely as cartilage, yet the cartilage is not converted into bone but is destroyed and part passu its place taken by bone.2 There is overlying the heart of a child at ' Reference is made to the after-birth, which includes the structures known anatomically as the umbilical cord, the amnion (the "caul" of the midwife), the chorion Iteve, and the fetal placenta. ^ The conversion of cartilage into bone was studied by many investigators especially between 1845 and 1870, and was the subject of prolonged and ani- 6 82 AGE, GROWTH, AND DEATH birth a well-developed gland known as the thymus. After childhood this undergoes a retrograde develop- ment ; 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 phe- nomenon 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 famil- iar 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 phys- iologically indispensable, for the material which the blood corpuscles furnish is used in many ways. For instance, the pigment which occurs in the hair is sup- posed to be derived from the chemical substances the use of which the body obtains by destroying blood mated debates, one might almost say of constant controversy. This need not be wondered at for the changes involved are very complicated, owing to the fact that the formation and destruction of cartilage, the formation of new and the removal of old bone, and the development of a new tissue (marrow) all go along together, and often may all be seen at once, each in various phases, within the limits of a single microscopic field of view. Our present knowledge renders it certain that the cartilage degenerates, dies, and disappears and takes no share in the production of bone. That certain rare exceptions to this rule occur has been maintained, but the evidence is, in my opinion, unconvincing. THE CELLULAR CHANGES OF AGE ^^^ corpuscles. One of the most familiar instances of des- truction is that of the tail of the tadpole. The young frog and the young toad durmg 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 ulti- mately altogether. ^ It is evident that such a vast amount of destruc- tion 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 considera- tion of the phenomenon of regeneration and of the repair of parts. These phenomena we can better take up later in our course, after we shall 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. 84 ' AGE, GROWTH, AND DEATH Old age, after what I have said, I think you will all recognise 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 no- tion. 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 cyto- morphic 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 differ- entiation lies the explanation of a great many of the known phenomena of biology, 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 CELLULAR CHANGES OF AGE 85 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 devel- opment 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. Ill THE RATE OF GROWTH L A DIES AND GENTLEMEN: In the first of the lectures, I described those grosser character- istics of old age, which we ourselves can readily dis- tinguish, or which an anatomical study of the body reveals to us. In the second lecture I spoke of the microscopic alterations which occur in the body as it changes from youth to old age. But besides the changes which we have already reviewed, there are those others, very conspicuous and somewhat known to us all, which we gather together under the com- prehensive term of growth. It is growth which I shall ask you to study with me this evening, and I shall hope, by the aid of our study, to reinforce in your minds the conclusion which I have already indicated, that the early period of life is a period of rapid decline, and that the late period of life is one of slow decline. In order to study growth accurately, it is desirable, of course, to measure it, but since we are concerned with the general problem of growth, we wish no par- tial measure, such as that of the height alone would 86 THE RATE OF GROWTH 87 be. And indeed, if we take any such partial measure, how could we compare different forms with one an- other? The height of a horse is not comparable to that of a man ; the height of a caterpillar is not comparable to that of any vertebrate. Naturally, therefore, we take to measuring the weight, which represents the total mass of the living body, and en- ables us at least with some degree of accuracy to compare animals of different sorts with one another. Now in studying this question of the increase of weight in animals, as their age increases, it is obvi- ously desirable to eliminate from our experiments all disturbing factors which might affect the rate of growth or cause it to assume irregularities which are not mherent either in the organisation of the animal or in the changes age produces. The animals which belong to the vertebrate sub-kingdom, of which we ourselves are members, can be grouped in two large divisions according to the natural temperature of their bodies. The lower vertebrates, the fishes, frogs, and their kin, are animals which depend for their body temperature more or less on the medium in which they live. The other division of vertebrate animals, which includes all the higher forms, are so organised that they have within certain limits the power of regulating their own body temperature. Now it is easily to be observed — and any one who has made observations upon the growth of animals can confirm this — that animals otherwise alike will grow at different speeds at different temperatures. 88 AGE, GROWTH, AND DEATH There are animals, like the frogs and salamanders, which will live at a very considerable range of tem- perature and thrive, apparently. No ultimate injury is done to them by a change of their bodily tempera- FiG. 26. Four Tadpoles of the European Frog A'ana fiisca. After Oskar Hertwig. The four animals are all of the same age (three days) and raised from the same batch of eggs, but have been kept at different temperatures. A at IT. 5° centigrade. j5 at 15.0° centigrade C " 20.0° " -Z? " 24.0° " ture. Here we have four young tadpoles, (Fig. 26), all of which are exactly three days old. The first of these has been kept at a temperature not much above freezing; the fourth at a temperature of about twenty- THE RATE OF GROWTH 89 four degrees centigrade ; the other two at temperatures between. They are all descendants from the same batch of frogs' eggs, and you can see readily that the first one is still essentially nothing but an ^gg. The second one, which has had a little higher temperature, already shows some traces of organisation, and those familiar with the development of these animals can see in the markings upon the surface the first indica- tions of the differentiation of the nervous system. The third has been kept at a considerably warmer temperature, and is now obviously a young tadpole ; here are the eyes, the rudimentary gills, the tail, etc. While the fourth tadpole, which was maintained at the best temperature for the growth of these animals, has advanced enormously in its development. Ob- viously, should we make experiments upon animals of this class it would be necessary to keep them at a uniform temperature, if we wished to study their rate of development, and that is, for very practical rea- sons, extremely difficult and unsatisfactory. Far bet- ter it has seemed for our study of growth to turn to those animals which regulate their own tempera- ture. This, accordingly, I have done, and the animal chosen for these studies was the guinea-pig, a crea- ture which offers for such investigations certain de- finite advantages. It is easily kept ; it is apt to remain, with proper care, in good health. Its food is obtainable at all seasons of the year, in great abundance, and at small expense. The animals them- selves being of moderate size do not, of course, re- 90 AGE, GROWTH, AND DEATH quire such extraordinary amounts of food as the large animals, should we experiment with them. Ac- cordingly with guinea-pigs I began making, years ago, a long series of records, taking from day to day, later from week to week, and then, as the animals grew older, month by month, the weight of recorded individuals. There was thus obtained a body of statistics which rendered it possible to form some idea of the rapidity of growth of this species of mammal. Now in regard to the rapidity of growth, it is en- cessary that we form clearer notions than perhaps you started out with when you came into the hall this evening. I will ask for the next of our pictures on the screen, where we shall see illustrated to us older methods of recording the progressive growth of animals. Fig. 27 is a chart taken from the records of my friend, Dr. Henry P. Bowditch, showing the growth of school children in Boston. Here we have, in the lower part of the figure, the two curves of growth in weight. The upper curve is the weight of boys. We can follow it back through the succession of years down to the age of five and one half years, when the records begin. The child weighs, as you see, a little under forty pounds at that time. When the boy reaches the age of eighteen and one half years, he approaches the adult size, and weighs well over 130 pounds. Here then we see growth repre- sented to us in the old way, the progressive increase of the animal as it goes along through the succession THE RATE OF GROWTH 91 of years. Now this is a way which records the actual facts satisfactorily. It shows the progressive changes of weight as they really occur ; but it does not give im,. 64 62 60 58 56 54 52 50 48 46 44 42 40 .A r^ ^-j Hflm 140 ISO 120 110 100 90 80 70 60 50 40 ooyy^ / QiA^ ^ /,.. • ••O-"' ■^^^ — ' d' / / /ScrM ^ r^ j^ - ^ / / 9^ --0 ^ /' /•' ^ ^•' °/ ^ / p / /■ / -' . / /' •^'' g-' -^ ^■ ^■" ~^.. 'Tto-'' ^tif-' '^ ^ 5 6 7 8 9 10 II 12 13 14 15 16 17 18 l£ Fig. 27. Curves Showing the Growth of Boston School Children IN Height and Weight. — After H. P. Bowditch. US a correct impression of the rate of growth. Con- cerning the rate of growth, some more definite notion must be established in our minds before we can be said to have an adequate conception of the meaning of that term.^ It is from the study of the statistics ' The method described in the text of determining the rate of growth was 92 AGE, GROWTH, AND DEATH of the guinea-pigs, and of other animals which I have since had an opportunity of experimenting with, that we get indeed a clearer insight as to what the rate of growth really is and really means. I should like to pause a moment to say that when I first published a paper upon the subject of growth, it, fortunately for me, interested the late Dr. Benja- min A. Gould. The experiments which I had made and recorded in that first publication came to a sud- den end, owing to a disaster for which I myself was personally not responsible, by which practically my entire stock of animals was suddenly destroyed. Dr. Gould, after consulting with me, proposed that I should have further aid from the National Academy of Sciences, and through his intervention I obtained a grant from the Bache fund of the Academy. That liberal grant enabled me to continue these researches, and this is the first comprehensive presentation of my results which I have attempted. In this and the subsequent lectures, I hope that enough of what is new in scientific conclusions may appear to make those to whose generosity I am indebted feel that it has been worthily applied. I cannot let such an oc. casion as this pass by without expressing publicly my gratitude to Dr. Gould for his encouragement and support at a time when I most keenly appreciated it. If animals grow, that which grows is of course the actual substance of the animal. Now we might say first defined and advocated by me in my article, " Senescence and Rejuvena- tion, "^(pMrw. of Physiol., vol. xii., pp. 97-153 (1891). THE RATE OF GROWTH 93 that given so much substance there should be equal speed of growth, and we should expect, possibly, to find that the speed would be more or less constant. I can perhaps illustrate my meaning more clearly, and briefly render it distinct in your minds, by saying that if the rate of growth, as I conceive it, should re- main constant, it would take an animal at every age just the same length of time to add ten per cent, to its weight ; it would not be a question whether a baby grew an ounce in a certain length of time, and a boy a pound in the same time, for the pound might not be the same percentage of advance to the boy that the ounce would be to the baby. In reality with an ad- vance of an ounce the baby might be growing faster than the older boy with the addition of the pound. To determine the rate I devised the following method.^ Take the weight at a given age, and the weight at the next older age for which there are observations. From these data calculate the average daily increase in v/eight for the period between the two determinations of the weight, then express the daily increase as a percentage of the weight at the beginning of the period. From a series of de- terminations the daily percentage increments are readily calculated for successive ages. Subsequently the method was modified for the study of the rate of growth in man by substituting the monthly, or even yearly, percentage increments for the daily. This method is not mathematically exact, since the grow- 94 AGE, GROWTH, AND DEATH ine weight is a variable function of the aoe, but it is sufficiently exact for our present needs, and has the advantages of simplicity and rapidity in its practical application. In the next slide (Fig. 28) which we are to see upon the screen we have my method of measuring the rate of growth illustrated graphically. There is here a curve which represents the rate of growth of male guinea-pigs. The figures at the bottom indicate the age of the animals in days. When guinea-pigs are born they are very far advanced in development, and the act of birth seems to be a physiological shock Pe^ice/Tviayae. JruybE/nie/n^. iTlale^. a 5811 n 23 29 35 38 45 60 75 90 105 120 135 ISO 165 UOday^ Fig. 28. Curve Showing the Daily Percentage Increments in Weight OF Male Guinea-pigs. from which the organism suffers, and there is a lessen- ing of the power of growth immediately after birth. But in two or three days the young are fully re- THE RATE OF GROWTH 95 covered, and after that restoration they can add over five per cent, to their weight in a single day. But by the time they are 17 days old, as represented by this line, they can add only four per cent, and by the time they are 24 days old, less than two per cent; at 45 barely over one per cent; at 70 still over one per cent; at 90 less; at 160 less; and towards the end the curve continues dropping off, coming gradually nearer and nearer to zero, to which it closely ap- proximates at the age of 240 days. In about a year, the guinea-pig attains nearly its full size. You notice that this curve is somewhat irregular. Such is very apt to be the result from statistics when the number of observations is not very large. It means simply that there was not a sufficiently large number of animals measured to give an absolutely even and regular set of averages. But the general course of the curve is very instructive. In the earlier condition of the young guinea-pig there is a rapid decline ; in the later, a slow decline. The change from rapid to slow decline is not sudden, but gradual, as you see by the general character of this curve. In the next slide (Fig. 29) we can see immediately that what I have asserted as true of the male is equally true of the female, althouorh the values which we have differ slightly in the two sexes, and there are accidental but not significant variations in this curve as in the first. Here also we observe at once an early period of rapid decline in which the rate of growth is going down and down — a period of slight decline in which, 96 AGE, GROWTH, AND DEATH to be sure, it is going down still, but with diminished rapidity. There is another method by which we can represent Pe/UjemjtcL^ Joa/yie/me/n^. J'^rrui/e<) 2 5811 n 23 29 3S3e +5 60 75 90 105 IZO 135 ISO 165 ISO I9S 2IOi:^a^ Fig. 29. Curve Showing the Daily Percentage Increments in Weight OF Female Guinea-pigs. this change in the rate of growth which will perhaps help to illustrate it ; and in the next of our pictures (Fig. 30) we see this other form of representation. The first vertical line represents the length of time which it takes a young male guinea-pig to add ten per cent, to its weight the first time. Here the third time — the fourth — the fifth — and you see as it is growing older and older it takes the animal longer and longer to add ten per cent, to its weight. Finally we get to the nineteenth addition, and we see that the period is very long indeed. How long that period is we can judge by the figures upon the left, which represent the length of the periods in days. THE RATE OF GROWTH 97 From the base line to the one marked "ten " is a pe- riod of ten days, and you see that the guinea-pig in adding to its weight ten per cent, for the nineteenth time does it so slowly that it requires ten days and more ; for the twenty-first time, nearly twenty ; for 50 Xem^o^ o^ W% -PeA^cod^. 7/ki^ 40 30 20 10 i^eAlod.'i 4^ 5 6 7 8 9 10 II 12 13 14 15 16 17 18 19 20 21 ZZ 23 24 25 Fig. 30. Curve Showing the Length of Time Required to Make Each Successive Increase of id per cent, in Weight by Male Guinea-pigs. the twenty-second time, nearly forty days. At last the number of observations becomes small, and the curve grows irregular. Thus we demonstrate that as the animal grows older it takes longer and longer to add ten per cent, to its weight. In the other sex, as the next slide shows, (Fig, 31), the same phenomena can be clearly demonstrated ; here are the periods as AGE, GROWTH, ANU DEATH before, lengthening out, as you see, at first ; then be- coming very long indeed. In the following slide I have another form of representation of this same phe- 70 JC^m^atA oi W% p€A.covU 3'€mta£&^. 60 50 40 30 20 J>eA-^^ " No. 12. 13 No. 6. 9^/2 " No. 13. ^4 No, 7. .» JQ H No, 14. 15 124 AGE, GROWTH, AND DEATH tinct eye, the protuberance caused by the heart. Nos. 1 1 and 12 show the embryonic shape at twelve and a half and at thirteen days — there has been a great in- crease of size with accompanying modifications of form. The next pair, Nos. 13 and 14, present us em- bryos of fourteen and fifteen days, respectively, and you see that the growth is very marked indeed, and the change of form obvious ; the creature is now pass- ing from the embryonic type into something resem- bling a rabbit. Other pictures could readily be added, but, though two weeks must still elapse before the animal will be ready to enter the world, it is not neces- sary for my present purpose to include this period in our survey. We need only contemplate, it seems to me, the series of drawings in Fig. 44 to realise that the early embryonic growth of the rabbit, like the embryonic growth of the chick, proceeds with a speed which is never paralleled by the growth during later stages. Now I had a considerable number of rabbit em- bryos preserved in alcohol, and though it was not very accurate to weigh them as alcoholic specimens, in or- der to determine their true weight, yet I resolved to do so as it was the best means at my disposal at the time. The result of that weighing was very in- teresting to me, becaused it showed that in the period of nine to fifteen days the rabbits had, on an average, added 704 per cent, to their weight daily ; but in the period of from fifteen to twenty days, the addition is very much less than this, only 212 per cent. But these rabbits at ten days have already had a consid- THE RATE OF GROWTH 125 erable period of development behind them, and as we have discovered that the younger the animal the more rapid its growth, we are safe, it seems to me — since we have learned that from the tenth to the fifteenth day there is a daily increase of over 700 per cent. — in assuming that in yet younger rabbits an increase of 1000 per cent, per day actually occurs. That is not so extraordinary an assumption, for bacteria are known to divide every half-hour, and if the little bacterium divides and grows up to full size in half an hour, and then divides again, it means that within a half-hour one bacterium has become two, and has increased, obviously, 100 per cent.; and if those two ao^ain divide as before, we should have four bacteria at the end of an hour — an increase of 400 per cent, and at the end of another half-hour, of 800 per cent., and so on ever in geometrical progression. We learn, then, that bacteria may in a few hours add 1000 per cent, to their original weight, and it is not by any means an exorbitant demand upon our credulity to accept the conclusion that, in their early stages, rabbits and other mammals and birds are capable of growing at least 1000 per cent, a day. If this be true, and it doubtless is true, we can adopt it as a convenient basis for comparison. As we learned from the rate curves, which were projected upon the screen earlier during the hour, the male rabbit gains in one day shortly after birth nearly eighteen per cent. — seven- teen and four tenths per cent. — and the female rabbit gains nearly seventeen per cent. Now we can 126 AGE, GROWTH, AND DEATH estimate the loss very simply by deducting this rate, which is the capacity of the animal to grow persisting at birth, from its original capacity, which we assume to have been looo per cent, per day. And if we do that the result is obvious. Over 98 per cent, of the original growth power of the rabbit or of the chick has been lost at the time of birth or hatching, respec- tively, and the same thing is equally true of man. We start out at birth certainly with less than two per cent, of the original growth power with which we were endowed. Over 98 per cent, of the loss is accomplished before birth — less than two per cent, after birth. That, I think, Is a rather unexpected con- clusion, certainly not one which, until I began to study the subject more carefully, I in the least ex- pected ; and even now when I have become more familiar with It, it still fills me with astonishment, it is so different from the conception of the process of de- velopment as we commonly hold it, so different from our conclusions based on our acquaintance with the growth and progress of the individuals about us. We overlook the fact that the progress which each indi- vidual makes is the result of accumulation. It is as if money were put into the savings-bank; it grows and becomes larger, but the rate of interest does not alter. So too with us; we see there is an accumulation of this wealth of organisation which gives us our mature power. But as that accumulation goes on, our body seems to become, as it were, tired. We may com- pare it to a man building a wall. He begins at first THE RATE OF GROWTH 127 600/„ SOO/i 400% 300% 200% with great energy, full of vigour ; the wall goes up rapidly ; and as the la- bour continues fatio^ue comes into play. More- over, the wall grows higher, and it takes more effort and time to carry the material up to its top, and to continue to raise its heigfht, and so, as the wall grows higher and higher, it grows more slowly and ever more slowly, be- cause the obstacles to be overcome have in- creased with the very height of the wall itself. So it seems v/ith the in- crease of the orofanism ; with the increase of our development, the ob- stacles to our growth increase. How that is I shall hope to explain to you a little more clearly in the next lecture. We have one more slide, which I would like to show you Fig. 45. It indicates the rate of erowth in 128 AGE, GROWTH, AND DEATH man before birth as far as it can be determined without better knowledge than "I have at command. The time intervals in the diagram correspond to the so-called lunar months — the ten lunar months of prenatal life. Of our early development we know very little so far as statistics are concerned, but from the third month onward we have some records. It is found that from the third to the fourth month the increase is 600 per cent. Just contrast that with 200 per cent, added in one year after birth ; 600 per cent, in one month against 200 per cent, in one year. From the fourth to the fifth month it is scarcely over 200 per cent. It then becomes only a little more than 100. In the seventh month, less than 100 ; and finally in the ninth and tenth months, it becomes very small indeed, less than 20, so that during the prenatal life of man, as we have seen in the prenatal life of the rabbit and of the chick the decline in the power of growth is going on steadily all the time. I shall use the few remaining moments to report to you yet another bit of evidence of the originally enormous power of growth. It has been estimated that the germ of the mammal, with which the devel- opment commences, has a weight of 0.6 milligram; another estimate which I have found is of 0.3 milli- gram.'' Perhaps I can give you some idea of what this value means by telling you that if the weight of the original germ of a mammal is assumed to be 0.6 ' These estimates refer to the placental mammals only. My authorities are M. Muhlmann, Ueber die Utsache des Todes, 1900, p. 45, and Donaldson, Growth of the Brain, 1895, p. 60. THE RATE OF GROWTH 129 milligram, we could, according to the laws of the United States, send 50,000 such germs by letter postage for two cents. It would take 50,000 germs to make the weight of one letter. That perhaps will give you some impression of the extreme minuteness of the primitive germ. In the human species at the end of even a single month it is no longer merely a germ, but a young human being, very immature, of course, in its development, but already very much larger. I doubt — even after all that I have said this evening about the startling figures of growth for the earlier stages — I doubt if you are prepared for the fact that the growth of the germ up to the time of birth repre- sents an increase of over five million per cent. How much over five million per cent, we cannot calculate accurately, because we do not know accurately the weight of the original germ, but an increase of five million per cent, is not above the true value.^ Con- trast that with anything which occurs in the later periods. What a vast change has happened ! What an imrriense loss has taken place ! The rate of this loss is evidently diminishing. The loss occurs with great rapidity in the young — less rapidly the older we become. Professor Richard Hertwig of Munich ~ has reached a similar result by a different method of calculation. He estimates the volume of the human fertilised ' Assuming the germ to weigh 0.0006 gramme, and the child at birth 3200 grammes, the percentage increment would be 5,400,000. '^ R. Hertwig, " Ueber die Ursache des Todes," reprinted from Allgemeine Zeitung, Dec. 12, 13, igo6 {Beilage). I30 AGE, GROWTH, AND DEATH ovum at 0.004 cubic millimetre and of the child at birth at 3 to 4,000,000 cubic millimetres, a billion times increase. Assuming the weight of a man of twenty years at 130 pounds, the increase after birth would be as 1:16. He thereupon emphasises the enormous diminution of cell production which must be assumed. It is a pleasure to have my own views confirmed by so distinguished a colleague. I attempted to convince you in the first and second lectures that that which we called the condition of old age, is merely the culmination of changes which have been going on from the first stage of the germ up to the adult, the old man or woman. All through life these changes continue. The result is senility. But if, as the phenomena of growth indicate to us so clearly, it be true that the decline is most rapid at first, then we must expect from the study of the very young stages to find a more favourable occasion for analysis of the factors which bring about the loss in the power of growth and of change as the final result of which we encounter the senile org-anism. Not from the study of the old, therefore, but from the study of the very young, of the young embryo, and of the germ, are we to expect insight into the compli- cated questions which we have begun to consider to- gether. I shall hope in the next lecture to prove to you that the supposition which has guided my own observations is correct, and to be able to show you that we do actually, from the study of the developing embryo, glean some revelations of the cause of old age. IV DIFFERENTIATION AND REJUVENATION TADIES AND GENTLEMEN: In order to present the subject of this evening, I will take a few brief moments at the beginning to review the results reached in the previous lecture. I spoke then of the phenomena of growth and endeavoured to make clear to you what I consider the fundamental con- ception of this study — that the decline in the growth power is extremely rapid at first and slow afterwards. This change in the rate of growth is of course due to things in the animal body itself. It is a logical con- clusion for us to draw that if we are to study out the cause of the loss of growth power, we should do it rather at that period of development when the change in the rate of growth is most rapid, for then we should expect those modifications to exhibit themselves most clearly because the magnitude of cause is likely to be proportionate to the magnitude of result, or, in other words, when the decline is most rapid, then we must expect to find the alterations which cause that decline in the organism to show themselves most conspicu- ously. You will remember, further, that we spoke of growing old as being a much more complicated ques 131 132 AGE, GROWTH, AND DEATH tion than one of growth alone, and that there occur, as the years advance, changes in the structure of the body. It is convenient to use one collective term for all these phenomena of becoming old, and that term, established by long usage, is senescence, the becoming old. What, therefore, we have to search for at present is a cause, a proximate cause at least, of senescence. In order to make the view I am to bring forward this evening quite clear to you, I must first of all take advantage of your kindness and recapitu- late briefly what I said in regard to cells, for you will remember that the cell is the foundation and unit of organic structure. With your permission I should like to recall more exactly to your minds what I said of the cells by having thrown upon the screen the slide which we saw before and which we used as an illustration of the cell. Here is the picture. Above we see the typical cell (No. i) from the oral epithelium of the salamander, and you remember in the centre this more conspicuous body with a granular and reticulated structure which we called the nucleus, and surrounding it is this mass which we called the body of the cell, or the protoplasm. Here (No. 2) is another condition of a cell of the skin of the salaman- der in which the nucleus presents a slightly different appearance. Here also we have quite a body of proto- plasm about the nucleus. Every cell consists of these two essential and fundamental parts, the nucleus and the protoplasm. Now the conclusion to which I shall gradually bring you by the facts to be laid before you L /o Fig. 46. Cells from the Mouth (Oral Epithelium) of the Sala. MANDER. — After Sobotta. i, recticulate stage ; 2, skein stage ; 3, 4, formation of the chromosomes ; 5, 6, formation of the equatorial plate ; 7, 8, division and migration of the chromosomes ; 9, reconstitution of the two daughter nuclei ; 10, completed division into two cells. 133 E34 AGE, GROWTH, AND DEATH this evening is that the increase of the protoplasm, together with its differentiation, is to be regarded as the explanation (or should we say cause) of sen- escence. Though protoplasm is the physical basis of life, though it is the actual living substance of the body, its undue increase beyond the growth of the nucleus changes the proportions of the two, and that change of proportion causes an alteration in the con- ditions of the living cell itself, and that alteration I in- terpret, as I shall explain more accurately later, as the cause of senescence, as the fundamental cause of old age. This slide (Fig. 46) also shows to us the early development of the cells through those phases which result in the multiplication of them. The nucleus changes in appearance and becomes a very different looking structure. These changes I need not now go through again. Suffice it to say that after the com- plicated alterations have completed their cycle, we get in the place of a single cell, two, and each has its own nucleus, and each its own protoplasm. Notice here that the two cells (No. 10) which finally result are smaller than the original cells from which they sprang, 'i'hese are by no means imaginary pictures, but accurate microscopic drawings from real cells of the salamander. The two cells which are thus pro- duced from one parent cell are characterised by their smaller size, and this smaller size applies not only to the cell as a whole, but likewise to its nucleus. After having been thus reduced in size, the nuclei and the cells will both expand, and soon the daughter cells DIFFERENTIATION AND REJUVENATION 135 will return to the mother dimension and be as large as the parent cell from the division of which they arose. There is thus, we learn, the constant fluctua- tion in the size of cells, a fluctuation in their di- mensions accompanying the process of cell division. Presently we shall have more to say in regard to this matter of the change in the cell in size. The next picture (Fig. 47) which I want to recall to you is one which we also had in an earlier lecture. It represents three slices through a very young rabbit before any of the organs of the animal have begun to develop. We can see here clearly the nuclei, as I pointed out to you before, nearly uniform in struc- ture, and you notice that the protoplasm around each nucleus is quite small in amount. If you will recall the previous picture (Fig. 46) of the skin of the sala- rhander, upon the screen a moment ago, you will realise immediately, in comparing the two, that in these young cells the proportion of the protoplasm to the nucleus is very small. That is again one of the fundamental facts to which we shall recur in a mo- ment. I wanted to show you this picture in order to revive in your minds the conception which I en- deavoured to give you before of the undifferentiated tissue, where the cells have nuclei pretty uniform in appearance and in size, each with its little mass of pro- toplasm about it, and this protoplasm appearing in all the cells under microscopic examination very much the same. We cannot in this stage of development say of a given cell that it displays structure by which, 136 AGE, GROWTH, AND DEATH ' If we saw the cell isolated under the microscope, we could determine from what part of the young em- bryonic body it was derived. When we see a cell ■''" ;© o -g^^:^ . f. . <=> -^^. .S,® :,:i?^ ::^,.::-^^^^ ,...5---^ -^ .^^/^,^,j.%£.i^C;wi^;:c£s^©-^^^^ c .. e 14^. -'- o . © ^ © . -^---©ir^^^C!. ■"*r». Fig. 47. Three Sections through a Rabbit Embryo of Seven and One Half Days. For explanation, see Fig. g, of which this is a repetition. from the adult we can determine its orig-in in most cases with certainty by its microscopic appearance Fig. 48 A. Entamaba histolytica^ highly MAGNIFIED, Living specimen drawn from a cover-glass preparation from a twenty-four-hour culture, by E. S. Kilgore. X Fig. 48. B. Preserved Specimen OF Entamaba histolytica, artificially coloured to demonstrate the large round nucleus. Same magnification as Fig. 48 A. — From a preparation loaned by Dr. Councilman. 137 138 AGE, GROWTH, AND DEATH alone. As development progresses, the simple con. dition of the cells is gradually obliterated, but we find another condition arising which we call the differ- entiated one. Differentiation is a process which goes on in the body as a whole, but of course it is also a function of each individual cell. We can see something of the process of differen- tiation if we study the unicellular organisms, those creatures, each of which Is complete in itself, although it consists of but a single cell, not of countless mil- lions of cells as we do. The picture. Fig. 48, which I have chosen to throw upon the screen, is one which I think may have an additional interest to you, for it is a photograph from the living cell known as the parasite producing dysentery. Its name is £n- tamceba histolytica. Fig. 48 A is drawn from a living specimen, which had thrown out three short protuber- ances {pseudopodid) and had swallowed some foreign body, which shows as a rounded dark mass. As the nucleus did not show in this specimen. Fig. 48 B has been added, a drawing from an individual which had been preserved and artificially stained, by which double treatment, as you see, the nucleus has been rendered conspicuous.^ Of course in the living specimen the nucleus was equally present although hidden by over- lying granules. Our Amceba is a unicellular parasitic ' It gives me pleasure to thank Dr. W. T. Councilman for the loan of this specimen, obtained from the intestine of a fatal case of amoebic dysentery. It is on Dr. Councilman's brilliant investigations that our knowledge of this disease is based. DIFFERENTIA TION AND REJUVENA TION 1 3 9 organism with scarcely any differentiation of its struc- ture. The next of the slides shows us again another of these parasitic simple organisms, namely Plasmo- diziTn vivax, the cause of tertian malarial fever. The tiny creature inhabits the blood corpuscles of man ; Fig. 4q. Tertian Malarial Parasite, Two human blood corpuscles alongside and drawn on the same scale, by E. S. Kilgore. when it enters the corpuscle it is very minute, scarce an eighth of the diameter of the corpuscle ; it grows very rapidly, feeding on and destroying the corpuscle and yet meanwhile by its own growth caus- ing the corpuscle to enlarge. Our picture. Fig. 49, shows three human red blood corpuscles, two in their normal condition, the third (on the right) distended by the overgrown parasite, which is heavily charged with pigmented granules, and almost completely fills the corpuscle. The nucleus at this stage of the 140 AGE, GROWTH, AND DEATH parasite's development is distributed as a series of small scattered granules, which cannot be demon- strated satisfactorily until they have been artificially coloured. The parasite itself is a small mass of un- differentiated protoplasm. In another stage of its life cycle the Plasmodium vivax has a distinct nucleus with only a very little protoplasm, and while in that stage it multiplies with that enormous rapidity which renders it such a dangerous parasite to the human race. I will now show you another picture of parasites Fig. 50. Trypanosot?ia Lewisi, from the rat's blood, with two blood corpuscles alongside drawn on the same scale, by E. S. Kilgore. — one form of which, in a related species, occurs in man. This particular form is one which occurs in the rat and is called the Trypanosoma. You can see that the body, instead of being a small and simple struc- ture, has elongated, acquired a peculiar form, and DIFFERENTIATION AND REJUVENATION 141 here in the interior are hghter and darker spots. These do not show very clearly in the picture, because it is from a photograph of a living specimen under the microscope. The lighter and darker spots corre- spond to the details in the structure of the organism. B imiii Fig. 51. Stentor caruleus; A, cut into three pieces; B, regeneration of the first piece; C, of the middle piece; D, of the posterior piece. After Gruber. Here is the tail of the organism, twisted, as you see, and in life capable of being bent. The movement of the animals in the natural fluid in which they are suspended is quite active. Alongside are some blood corpuscles; the figure is magnified about the same as 142 AGE, GROWTH, AND DEATH the one of the malarial parasite which I showed you a few moments ago. The next slide, Fig. 5 1, exhibits an organism which swims free in the water, and is pretty well shown in this figure. It is called the Stentor, Fig. 51, y^. Here the chain of beads represents the nucleus. The peculiar shape of the nucleus is a con- stant characteristic of this animal. Upon the surface of the body there are fine lines indicating superficial structure. At the top there occurs what we call the mouth. Over the rest of this minute oro-anism there is a thin cuticle, but at the mouth the cuticle is absent, and the protoplasm is naked or uncovered so that food can be taken in. There are bands of hairs showing coarse and stiff in the figure but capable of movement, and with the aid of its vibratile hairs, or cilia, the organism can swim about in water. There is another internal structure, the vacuole, shown in the upper part of ^ as a circle. Obviously in an animal like this we no longer have simple protoplasm alone, but protoplasm in part changed into other things. Here then within the territory of a single cell we have differentiation. If now in these unicellular organisms we study both the protoplasm and the nucleus, we learn that most of these modifications which are so conspicuous upon microscopic observation are due to changes in the protoplasm. It is the protoplasm which acquires a new structure. In the resting nu- cleus, on the contrary, we find perhaps a change of form, minor details of arrangement by which one sort of nucleus, or one stage of the nucleus, can be distin- DIFFERENTIATION AND REJUVENATION 143 gulshed from another, but always the nucleus consists of the same fundamental constants. There is the membrane bounding it ; there is the sap or juice in the interior, and there is the network of living threads stretching across it. Here and there imbedded in and connected with the network are spots of a special substance, which we call chromatin. These four things exist in the nuclei and are apparently always present, and there is usually not to be seen in the resting nucleus anything of change comparable, in extent at least, with the change which goes on in the protoplasm — on the other hand, the protoplasm ac- quires items of structure which were totally absent from it before. The nucleus rearranges its parts rather than changes them. This is a very important fact, and shows us, if we confine our attention even to these little organisms only, that the differentiation of the protoplasm is quantitatively the more important of the two — the differentiation of the nucleus the less important. We can now turn from a consideration of these low organisms to the higher forms, among which we ourselves of course are counted, in which the body is formed by a very considerable number of cells. Again I should like to take advantange of your kind- ness and show you some of the pictures we have already reviewed, in order to utilise the features which they show as illustrations of the fundamental principle that the conspicuous change is in the proto- plasm. First we have nerve cells. Fig. 52. In the 144 AGE^ GROWTH, AND DEATH two upper drawings are represented two isolated nerve cells, to show their shape. They have been coloured by a special process ^ so dark that the nucleus which they contain in their interior is hidden from our view ; it is of course none the less there. This dark staining enables us to trace out the shape of these cells very clearly, and you can see that instead of being round and simple in form they have their elongated processes stretching out to a very consid- erable distance ; these processes serve to catch up from remote places nervous impulses and carry them into the body of the cell, and thus assist in the work of nervous transmission. The elongation of these threads is, as you see, adapted, like the elongation of a Mfire, to long-distance communication. Here are two other figures which represent nerve cells treated by a different process,'^ and again artificially coloured. But the colour in this case has attacked certain spots in the protoplasm, consequently we see that the pro- toplasm around the nucleus in both of these figures is no longer simple and uniform, but contains these de- posits of dark-coloured material.^ Below are three other nerve cells ; the one in the centre shows you the accumulation, /, of pigmented matter in the protoplasm , again an index of change because the previous uniformity has been replaced by diversity in the composition of the various parts of the single cell. 1 Carmine. ^ Nissl's methylene blue method. ^ The " tigroid markings" — compare p. 54. i i 1 ^V^ J ^ ^^\ \ ■i 1 ;^ 1 -X 1 \ ! IlfJ 7. '^ i , /,-, / i • /} / . ^.. % 1 J '-'^1 -^^ ^ ,' • # . 1')' FicjJ. I':(I.-'J. Fic/.o , Fig. 52. Various Kinds of Human Nerve Cells. — After Sobotta. I. Two isolated multipolar ganglion cells from the human spinal cord. X ifeo diams. 2. Two multipolar ganglion cells from the lumbar en- largement of the spinal cord of a child. X 480 diams. 3. Three cells from a human spinal ganglion, stained with haematoxyline and cosine. X 420 diams. ID 145 146 AGE, GROWTH, AND DEATH Figure 1 1, p. 50, shows us more clearly the principle of structure of a nerve cell, for there we have the central body of the cell composed of protoplasm with its nu- cleus in the middle and a s,mall spot in the centre of the nucleus, and the long branching processes running out in all directions which can take up nerve impulses from other similar or dissimilar cells, as the case may be, and carry them to the central body. To carry the message out there is typically but one process, which is different in appearance from the other processes which carry the impulses in. The latter are branch- ing and are therefore called the tree-like or dendritic processes. Here is a single process (Fig. 11, Ax) like a long thread to carry the impulses away, and which is called the axon of the nerve cell. In this case the modification of the shape of the cell has adapted it to the better performance of its functions. Notice also in these cells the enormous increase in the amount of protoplasm as compared with the nu- cleus. In the young cell of the rabbit germ, of which I showed you several illustrations a few moments ago, we had very little protoplasm for each nucleus, but here the protoplasm has many, many times the volume of the nucleus, and this is a relatively old cell.^ Next let us look again at the figure of the striated ' The nerve fibres of vertebrates are usually each surrounded by a protective covering of cells, making a sheath. Kolliker pointed out in 1886 that the sheath cells are very small in young embryonic stages and that their size increases with age, owing not to the growth of the nuclei, but to the growth of the cell body, including the myelin, the special substance which characterises the dif- ferentiation of these cells. See " llistologische Studien an Batrachier Larven," Zeitschr . fiir wiss. Zoologie, xliii., p. 1. DIFFERENTIATION AND REJUVENATION 147 muscle fibre, Fig. 53, which you may recall from the second lecture, so that it will suf^ce if your atten- tion is again directed to the oval nuclei, and to the lines stretching crosswise on the muscle giving it a " striated " appearance. You re- member, doubtless, that such fi- bres are the ones which enable us to make voluntary motions. Orig- inally each fibre was a set of cells, and the cells had some protoplasm, but, gradually, as development pro- gressed, there appeared in them longitudinal fibrils different from the protoplasm, and the fibrils also created ultimately the appear- ance of cross lines on the fibre. T • 1 i^i M 1 • 1 r 1 ^^°- 53- Part OF A It IS the hbrils which perform the human muscle fibre. muscular contractions. It is not the original unmodified protoplasm, but the modified or differentiated muscular cell which is capable of vol- untary contraction. The next picture, Fig. 54, shows us clearly and strikingly how much the differentiation may vary. We have here another type of differentiation. These are gland cells ; we can see here, as I pointed out to you before, the material in the form of granules, which is to produce the secretion from these gland cells. This is an orbital gland, and here are the cells, which are very much smaller because they have discharged 148 AGE, GROWTH, AND DEATH their secretion and are very conspicuous on account of their dark colour. Three typical cells are repre- sented separately (Fig. 55). The first shows us a cell full of the material which is to be discharged and is to form a part of the salivary secretion. The second is a cell which has partly lost its accumulated material, and the third is one which has discharged it almost completely, so that it has be- come very much reduced in size. We learn from these ob- servations and others similar that the size of cells may vary also according to their func- tional condition. Let me refer back to an earlier picture (Fig. 16J representing a section of the so-called salivary gland of the intestine, better termed the pancreas. Here we can see for each of these cells a nucleus and a body divided into two parts, a darker portion around the nucleus and a lighter part with little granules in it, which represents the accumu- lation of material which is to form the secretion. When the cells have discharged their secretion, they, like the Fig. 54. Section from an Orbital Gland of a Dog — After Lavdowsky. Fig. 55. Diagram of Three Cells of a Sal- ivary Gland, to Illus- trate THE Change Re- sulting from the Dis- charge of the Secretion. DIFFERENTIATION AND REJUVENATION 149 cells in the salivary gland, are found to have dimin- ished in size and become very much smaller indeed than they were in their earlier state when charged with the zymogen destined to be given out. In this case also we have an illustration of a functional variation in the size of the cells. This ends the series of pictures which I wanted especially to show to you as illustratinor the changes of the cells as their differ- entiation progresses. We can see in the bodies of the cells the changes which have occurred. Here is a picture (Fig. 56) which teaches us one thing more about these cells. Notice the scattered nuclei, each surrounded by protoplasm, completing the cell. The protoplasm of each of these cells is connected across with the protoplasm coming from another, so that the whole set of cells forms an ir- regular protoplasmic network. Now in the spaces between these cells are fine lines. These represent delicate structures which we call connective tissue fibrils, which have a mechanical function. By their tensile strength, their power to resist a pull, they give a certain supporting power to the tissues. Our pic- ture represents one of the tissues which support and connect other portions of the body. Now the fibrils apparently lie entirely disconnected from the cells, but a more careful study of the history of the con- nective tissue has revealed the very interesting and instructive fact that the fibrils, now separate from the cells, arose by a metamorphosis of the protoplasm of the cells — that they are first formed out of some of 15° AGE, GROWTH, AND DEATH the protoplasm of these cells, then split off from them, and come to lie in the intercellular regions, so that here we have another type of cell differentiation brought to our notice, one in which the product is separated from the parent body to which it owes its origin. Now you will perceive immediately, if you recall the series of pictures which have just passed ■^ /f^^^J^^^^. >^A ^-'rT, \^w '< V'd y ^,.«=/(^^f' '.vy^;|^ijj ^.'■^■^/F//''' rV ., 1/ If :^V;- w//'ri7j/('. Anat.,y\\\., 82-152, Taf.VII.-IX. His observations have been abundantly confirmed by later investigators. Fig. 65. Section of a Gland of the Large Intestine of an Adult Cat. or, orifice of the gland, wz, dividing nuclei (mitotic figures). 130 diameters.. 193 194 AGE, GROWTH, AND DEATH the top, the cells are cast off. I have already spoken of the enormous loss of cells from the lining of the digestive canal which occurs throughout life. 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 organisation, 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 cannot attain the differentiation of compli- cated 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 tiny caterpillar must take care of 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 secre- tion 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 al- ready established ; but, as we have learned, differen- tiation impedes growth. In other words, in such a larva the multiplication of cells is held back by the very demands of the condition 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. REGENERATION AND DEATH 195 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 &gg of the salamander, which I showed you upon the screen, you will remember that that is a structure of consider- able 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 diges- tive process is necessary than that inherent in all living protoplasm. So the young salamanders develop under most advantageous conditions, and can actually pro- duce 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 the accumulation of food for the nourishment of the germ is carried yet further. As you know, the ^'gg of the bird is much bigger than that of the salamander. Again, in the highest ani- mals, in the placental mammals, there are other special contrivances which nature has introduced to secure 196 AGE, GROWTH, AND DEATH ample and adequate nourishment of the developing germ. By means of the placenta the uterine period has been lengthened, and the embryo is nourished at the expense of the mother with little physiological exertion on its own part. Moreover, in all mammals lactation and maternal care serve to further prolong the developmental period. By these means the pro- tective processes have been wonderfully perfected and the result is that in mammals there is a long period during which the production of cells goes on ; the cells at first all remain relatively simple, and by the time they begin to change the number of cells is so great that the possibilities of an almost infinite variety of peculiarities in them are given. There are cells enough to allow this variety to be worked out. This type of development we call the embryonic. We know, therefore, that nature has recognised a restric- tion which she herself has put upon development, the restriction which obliges development, if it is to be ample, to prolong the accumulation of the undifferen- tiated cells. In response to this condition, she has instituted for higher types of animals that development which we call embryonic, leaving for the lower types that development which we call larval.^ Thus we meet in the growth and formation of the higher ani- mals, and in the history of the comparative develop- ' The comparison between the larval and embryonic types of development was first made by me in 1895, " Ueber die Vererbung und Verjiingung,'' Bio- logisches Ceniralblatt., xv., 571-5S7 ; translation in American Naturalist, xxx., 1-9, 89-101. REGENERATION AND DEATH 197 ment of the animal kingdom, fresh illustrations of the great importance of the young type of cells. We can learn the same thing from the study of regeneration. The regenerative process depends to a large extent upon partial differentiation, or even upon its total absence. Regeneration is a most in- teresting and wonderful process. I took pains only this afternoon to look at that famous classic by Trembley ^ on hydroids, or polyps as he called them. T/ie Fresh- Water Polyps, a book published in 1 744, was well printed, and on such good paper that it looks to-day almost like a new book. He per- formed 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 start- ling 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 ^ Me'moire pour servir a V histoire d' tm genre de polypes d' eau douce a bras en forme des carnes, par A. Trembley, de la Societe Roiale, a Leide, MDCCXLIV., 4to, pp. xvi., 324 ; 13 plates. A German translation by J. A. E. Goeze was published at Quedlinburg in 1775. Abraham Trembley was born at Geneva, Switzerland, in 1700 and died there in 17S4. His famous experiments were made in Holland while he was engaged as a tutor in the family of Count Bentinck. 198 AGE, GROWTH, AND DEATH earthworm, and even among vertebrates ; for he it was that proved 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 or the leg of a salamander, a new tail, or a new leg, as the case may be, would o-row out. He also made similar experiments on the Fig. 66. Vignette from Trembley's Classic Memoir, representing Trembley making his experiments on regeneration in fresh-water polyps. regeneration of the tail in tadpoles. 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. These examples may * Lazaro Spallanzani, Prodromo di un opera da imprimersi sopra le repro- duzione atiimali, 8vo, Modena, pp. I02, 1768, (French translation by de la Sabionne, Geneva, 1768. English translation. Aft Essay on Anijnal Repro- atictions, 8vo, London, 1769, pp. 86. The " Prodromo " has been repub- lished in volume four of Spallanzani's Opcre Scelte.) REGENERATION AND DEATH 199 suffice to indicate to you 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. Let us consider first unicellular regener- ation, and accordingly we pass to the examination of B Fig. 67. Stentor. the next of our slides, which represents a creature of the kind called Stentor, Fig. 67. It is a single cell. The nucleus of the cell has a singular form, for it con- sists of nine bead-like enlargements, with the parts between constricted to mere delicate connecting 200 AGE, GROWTH, AND DEATH threads ; its protoplasmic body is large, and some- thing of its structure I have told you in a previous lecture. A German investigator, Professor Gruber, has succeeded in dividing one of these Sten- tors, 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 restored itself and became a complete Stentor. In such experiments the proto- plasm around 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. Another example of unicellular regeneration is of- fered us by nerve fibres. A nerve fibre is a thread- like prolongation of a nerve cell (neurone) and is of course a part of the cell, as much so as the proto- plasmic body immediately surrounding the nucleus. When a nerve is cut across, as happens, for instance, necessarily in every surgical operation, the nerve fi- bres are severed. The part which is separated from the central cell dies by a degenerative process, the part which is connected with the cell, on the contrary, may grow and elongate itself. In other words, the cell regenerates the part which it lost, just as a sala- REGENERATION AND DEATH 201 mander may regenerate its lost tail. By the growth of nerve fibres a whole nerve may be regenerated, a fact which is often of the utmost practical medical and surgical importance. Many researches upon the re- generation of nerves have been made, and some questions about it are still subject to dispute, but I have confined myself to such statements as seem to me beyond controversy. Our next picture demonstrates a similar phenom- enon. It represents muscle fibres which have been injured. Every muscle fibre contains in its interior its contractile substance, the fibrils, in regard to which I have already spoken to you ; but it also contains a certain amount of substance which is still undiffer- entiated protoplasm. Now when a muscle fibre of this sort is injured, we find that the muscular struc- ture, 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, a, b. This may happen at the end of a muscle fibre — e, f- — producing there a considerable mass of protoplasm, with nuclei multiplying in it ; or we may find a chain of nuclei, each with its separate protoplasmic body, b ; such nuclei will multiply. When the increase of the un- differentiated protoplasm has gone on far enough, the injured muscle will produce again the muscular sub- stance proper — the contractile fibrils. Muscular fibre, in other words, can be regenerated by itself, but only by the growth of its undifferentiated portion ; the 202 AGE, GROWTH, AND DEATH fibrillated or differentiated portion of a muscular fibre has no regenerative power. ^ Let us re-examine another figure, Fig. 69. Here is represented the lining layer of the oesophagus with the cells composing it, the upper ones being horny, Fig. 68. Striated Muscle Fibres in Process of Regeneration. a, b, three days after rupture of the muscle; c, eight days after rupture; d, 26 days; ^, lo days;/, 21 days;^, 43 days. — After Ernst Ziegler. X 35° diameters. 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 1 The regeneration of muscle fibres has been studied hitherto mainly by pathologists, for in the higher animals muscular regeneration occurs chiefly as the sequel of injury to the muscle fibres, injury either mechanical or from path- ological causes, as, for example, in abdominal typhus. The literature of the REGENERATION AND DEATH 203 comes from the country and has never seen a train ; drive him to the station, and are frightened, perhaps, because the horse himself is so much alarmed — pos- sibly have a narrow escape because of the excitement <3 CD f«/j(r^^»«^a^. Woch- enschri/t, 1900, p. 783. Alex. Schmincke, "Die Regeneration der quergestreiften Muskelfasern bei den Wirbelthieren. Einevergleichendpathologische Studie. I. Ichthyopsiden," Verhandl. Fhys.-tned. GesellscJiaft Wfirzbiirg, N. A,xxxix., 15-130, Tafel 1., II. (Gives an exhaustive review of previous investigations.) REGENERATION AND DEATH 205 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 physio- logical 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, re- generation 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 discovery, when made, is likely to prove of great practical im- portance. 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.i They are due to the inherent growth 1 A semi-popular exposition of this view regarding malignant tumors has been published by V. Dungern and R. Werner, Das Wesen de?- bosartigeti Gesch- willste. Eine biologische Studie, 8vo. pp. 159, Leipzig, 1907. 2o6 AGE, GROWTH, AND DEATH 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 com- plete if it confined its attention only to the power of growth in relation to cytomorphosis. It must also in- clude the contemplation and study of the regulatory power of the organs. Experiments are being made in many places, minds are at work in many laboratories upon this problem of the 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 solve the mystery of 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 applica- tion of our scientific discoveries in this field, — in other words, could we learn to regulate the formation and" growth of tumors, — we should say of it justly that it was as noteworthy a contribution to medical know- ledge as the discovery of the germs of disease, and would doubtless prove equally beneficial to mankind. Although, then, the .'tudy 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 REGENERATION AND DEATH 207 the useful applications of which are immediately obvious to every one. We find in the process of regeneration of organs or parts of the body that it is always the young cell which plays the principal part. This is beautifully illustrated in the picture upon the screen, Fig. 70. 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 crusta- ceans. It has on its head a little feeler which we call the antenna. The particular kind of arthropod, the antenna 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 are pic- tured the stages of the progressive restoration. Part of the antenna has been cut off in this case ; the wound was healed over here, No. i, 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 be- gin to shape themselves out. No. 3, b, and we see presently an accumulation of cells which is assuming 1 Ost, T-. " Zur Kenntniss der Regeneration der Extremitaten bei den Arthro- poden," Archiv f. Entwickehtn^smechanik, xxii., 289-324, pis. x-xii. Fig. 70. Longitudinal Sections through the An- tenna OF Oniscus IN Various Stages of Regeneration AFTER Amputation. — After Ost. a, cicatricial tissue ; b, regenerated tissue ; cu, cuticula, or outer shell ; gl, glands ; pig, pigment. Magnified. 208 REGENERATION AND DEATH 209 a definite form, No. 4, d, that in the next figure has clearly become the promise or beginning of a new ter- minal joint, Fig. 71, which will become free when at the next moult the old shell or cuticle is cast off. The minute study of this process has shown that the regenera- tion depends practically ex- clusively upon the cells of the young type, and that after they have grown out and ac- cumulated here in this man- ner, No. 3, d, some of them undergo differentiation, be- coming muscle cells ; others change in the manner indi- cated here, No. 4, where we see a commencing alteration of the nuclei, which is further accented in Fig. 71, and leads , . r , 11 Fig. 71. Section through to such a groupmg of the cells ^ regenerating antenna of that the glands, which were C«?V Mary Isabelle Steele, " Regeneration in Compound Eyes of Crustacea," Jour. Exp. ZooL, v., 163-244, 16 pis. (1907). 2 C. Herbst, Ai-ch. f. Entwickelungsmechanik, ii., 455-516(1896). See also Bd. ix., 215-293 (1900). REGENERATION AND DEATH 211 mesenchyma, — scattered about in which are free sim- ple cells, ^ which are referred to by recent authors as "parenchymal" or "formative" cells. Now if the head or tail of a planarian be cut off, the part lost is regenerated. The regeneration is effected not by the growth of the old tissues, each producing of its own kind, but chiefly (perhaps wholly) by the multiplica- tion and differentiation of the " formative " cells which, after migrating to where they are needed, produce outer skin (epidermis), intestine, muscle, etc. They constitute a store of undifferentiated cells, ready to enter upon various active differentiations when occa- sion arises. There is a marine animal called Ciona : it belonofs to the class of the Ascidians. Professor Jacques Loeb 2 discovered in 1892 that if the portion of the animal containing the nerve ganglion, or rudimentary brain, be cut out, it will be regenerated, and a new brain formed. This discovery was confirmed by Pio Min- gazzini,^ a gifted Italian zoologist whose early death we lament. Recently, L. S. Schultze * has shown ' So far as known to me these ceils were first described by H. N. Moseley (" On the Anatomy and Histology of the Landplanarians of Ceylon." Philos. Transactions, 1874, p. 105). J. Keller in 1894 {Jeua'ische Zeiischr. f. Natur- wiss., xxvii,, 371-407) demonstrated their role in regeneration, Keller's inter- pretation has been confirmed by W. C. Curtis (/"rt^r. Boston Soc. Nat. History, XXX., pp. 515-559) and Miss N. M. Stevens {.4rc/i. f. Entwickehingsme- chanik, xxiv., 350-373, IQ07). The cells are of the embryonic type, that is to say, without any specialisation or differentiation. ^J. Loeb, Untersuchungen zur Physiologischen Morphologic, 1891—92. ^ P. Mingazzini, "Sulla regenerazione nei tunicati," Boll. Soc. Natur- alisti, Napoli, v. (1891.) 4 L. S. Schultze, " Die Regeneration des Ganglions bei Ciona intestinalis, L., 212 AGE, GROWTH, AND DEATH that the regeneration is accomplished by the growth of undifferentiated cells, which subsequently undergo differentiation. The cases of regeneration which we have re- viewed are all connected with the repair of injuries. But there are also cases known of spontaneous and normal regeneration, as they might be called. For example, there are certain fresh-water jointed worms, annelids, which produce in the midst of their body from time to time a budding zone, a narrow band of tissue intervening between two segments. The ante- rior part of the zone forms a new tail for the anterior part of the worm, the posterior part of the zone forms a new head for the posterior part of the worm ; division follows, and thus out of one worm two are produced. The external features of this wonderful process were described very well indeed in 1771, by the celebrated naturalist O. F. Mullen^ It was re- served for Carl Semper,^ under whom I had the hon- our to study in 1875-76, to demonstrate, at that very date, that the cells of the budding zone are of the embryonic type, and that after having multiplied sufficiently they begin to differentiate into the tissues und iiberdas Verhaltniss der Regeneration und der Knospung zur Keimblatt- lelire," Jena Hsche Zeiischrift, xxxiii., 263-344, Taf. XII., XIII. (1899). For our present purposes it is a matter of regret that on the cytological side Schultze's observations leave much to be desired. ' O. F. Miiller, Naturgeschichte einiger Wurmarten des siissen tmd salzigen Wassers, Kopenhagen, 1771. ^ Carl Semper, " Die Verwandschaften der gegliederten Thiere, III." Sem- per' s Arbeiten, Zool. Zootom. Inst. Wiirzburg, iii., 115. See especially p. ibiff. REGENERATION AND DEATH 213 necessary to complete the new tail and the new head. Through Professor Semper's kindness I had the privilege of seeing many of his preparations, and can therefore speak with confidence about his results. This completes the evidence which my time per- mits me to lay before you in order to convince you that the young type of cells really is physiologically and functionally important, that it really does possess the power of growth that 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 modifica- tion and change of structure which goes on in every individual of our species and of all the higher ani- mals. We are familiar with the death of cells. It occurs constantly and, as I have endeavoured to ex- plain 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 indi- vidual, is dead. The organ is alive and well, One 214 AGE, GROWTH, AND DEATH 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 the body was dead — but the heart lay upon the physio- logist's table, beating. The experimenter could sup- ply it with the necessary circulation. He could give stimuli to it, and under these favourable conditions make important discoveries in regard to the function- ing 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 re- gard 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 some- thing which we must familiarise ourselves with, and the great importance of which we must carefully ac- knowledge, for much of the benefit which the medi- cal 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 many of the lower organisms death does not ^Charles S. Minot, "Die Bildung der Kohlensaure innerhalb des ruhenden und erregten Muskels," Ludwig's Arbeiten der Physiol. Anstalt, Leipzig, xi., 1-24 (1876). REGENERATION AND DEATH 215 occur, so far as we at present know, as a natural and necessary result of life. Death with them is purely the result of an accident, some external cause. Our existing science leads us therefore to the conception that natural death has been acquired during the pro- cess of evolution of living organisms.^ 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 de- fended, by saying that it is due to differentiation, 2 that when the cells acquire the additional faculty of passing beyond the simple stage to the more com- plicated organisation, they lose some of their vital- ity, some of their power of growth, some of their possibilities of perpetuation ; and as the organisation in the process of evolution becomes higher and higher, the necessity for change becomes more and more imperative. But it involves the end. Differen- tiation leads up, as its inevitable conclusion, to death. Death is the price we are obliged to pay for our organisation, for the differentiation which exists in us. Is it too high a price ? To that organisation 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 in- 1 On death among Protozoa see Appendix No. III. 2 The theory that natural death is the incidental result of cellular differentia- tion was first put forward by me in 1885 ; compare Proceedings American Association Adv. Science, vol. xxxiv., p. 311. 2i6 AGE, GROWTH, AND DEATH debted 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 ; per- haps 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 essen- tial to those two states, science is utterly unable to REGENERATION AND DEATH 217 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 gen- eral aspects of our subject to present to you, and a formulation of the general conclusions toward which all the lectures have aimed. VI THE FOUR LAWS OF AGE T ADIES AND GENTLEMEN: I have re- ferred in these lectures repeatedly to the cell and its two component parts, the nucleus and the protoplasm. To-night I shall have only a few refer- ences to make directly to these, and shall pass on for the latter part of the hour to another class of con- siderations bearing upon the problem of age. Before we turn to these new considerations, however, I wish to say a few words by way of recapitulation concern- ing the changes in the cells as corresponding to age. Cells, as you know from what I have told you, un- dergo in the body for the greater part a progressive change which we call their differentiation. We may say that there are four kinds of cells for purposes of an elementary classification to be used in a simple ex- position like the present. The first kind are those cells of the young type, in which the protoplasm is simple, and shows as yet no trace of differentiation. These cells are capable of rapid multiplication, and some of them are found still persisting in various parts of the adult body, and serve to maintain the growth of the body in its mature stage. Another 218 THE FOUR LAWS OF AGE 219 class of cells presents to us the curious spectacle of a partial differentiation ; such are the muscle fibres by which we accomplish our voluntary movements. These fibres consisted originally only of protoplasm with the appropriate nuclei, but, as they are differen- tiated, part of the protoplasm changes into contractile substance. Another part remains pure protoplasm unaltered. If now the muscular or contractile por- tion of the fibre be destroyed, the undifferentiated part of the protoplasm then shows that it has still the power of growth. It has only been held back by the condition of organisation, and we perceive in the re- generation of these fibres evidence of the fact that so long as the protoplasm is undifferentiated it has the power of growth, which, however, does not reveal itself unless an opportunity is afforded. Third, we come to the cells which are moderately differentiated ; such, for instance, are the cells of the liver, and if for any reason a portion of the liver be injured by ac- cident or disease, we find that these partially differen- tiated cells reveal at once that they have a limited power of growth still left. If we pass on to the fourth class, that in which differentiation is carried to the highest extreme, we find that the cells do not have the power of multiplication. Such are the nerve cells by which the higher functions of the body are carried on. They represent the extreme of cellular differentiation, and almost never do we see these cells multiplying after the differentiation is accom- plished. Presented in this form, we then recognise, it 220 AGE, GROWTH, AND DEATH seems to me clearly, the effect of differentiation upon the growth of cells. The facts are clear as to their meaning-. We can, however, proceed a little farther than this, / -—- because we can actually ascertain, ( >^-v ... ' ] approximately at least, the rate at ') ?^- '-' ^ ^ which cells multiply. We accom- I plish this by determining the '?m- j^ ' totic index. The mitotic index is the number of cells to be found at any given moment in the active '^ j process of division out of a total of one thousand cells. ■""^ May I pause a moment to recall Fig 72. Portion of this picture to you and ask you to THE Outer Wall of a , ^ , -^ . -' . Primitive Muscular notice at this point the CUrious Segment of a Cat Em- , , 1 • 1 BRY00F4.6MM. Harvard darker spot which represents a fet7t,rk«?"ro": nucleus in process of division? The resting nuclei are oval. YoU wiU See it WOuld be easV in pale, and granular. i he _ •' dividing or mitotic nuclei, such a preparation as this to count of which there are ttixee, ., , . . .. are dark, irregular in out- the UUClei One by One UUtll One line, and ghow the chromo- ij , . ,1 i 1. somes. In this case the had got up to a thousand, and to dividing nuclei all lie near record, as oueweut alouP", how the inner surface 01 the ' &' wall. The picture iiius- many of the nuclei are in process trates the ease with which ...... mitotic figures may be re- of dlVlSlOU, for the nucleus m dl- cognised. ... .-, . , r^-, . Vision IS easily recognised. 1 his process of division is named mitosis : the figure which the nucleus presents while it is undergoing division we call a mitotic figure. Counting the dividing nuclei, we may determine that in a thousand cells there are a THE FOUR LAWS OF AGE 221 given number which have nuclei in process of divis- ion, and such a number I propose to call " the mitotic index,"- I wish now only to call to your attention this picture because it enables me to illustrate before you the method of measurino- the mitotic index. In the rabbit embryo at seven and one half days, I have found by actual count that there are in the outer layer of cells, known technically as the ectoderm, 18 of these divisions per thousand ; in the middle layer, technically the mesoderm, 1 7, and in the inner layer, the entoderm, 18. At ten days we find the number already reduced, and the figures are, respectively, 14, 13, and 15, and for the cells of the blood only 10. There has already been a great reduction. In the next phase of development (rabbit embryo of thirteen days), we find, however, that the parts are growing irregularly, some faster, some slower. We note that wherever a trace of differentiation has occurred, the rate of growth is diminished ; where that differentia- tion does not show itself, the rate of growth may even increase in order to acquire a certain special develop- ment of a particular part. So that instead of uni- formity of values for the mitotic index, we get a great variety. But, nevertheless, the general decline can be demonstrated by the figures. In the spinal cord the ' Cells are known to divide without mitotic figures appearing ; the process is then termed amitosis. Amitosis occurs in certain degenerating cells of mam- mals and is said to occur in sundry invertebrates as a normal process. So far as I am aware there is, however, at least as yet, no evidence that amitosis occurs in the embryos of the higher vertebrates. If it did occur it might diminish the validity of the mitotic index. 222 AGE, GROWTH, AND DEATH index is ii, in the general connective tissue of the body lo; for the cells of the liver ii; in the outside layer of the skin lo ; in the excretory organ 6 ; in the tissue which forms the centre of the limb also 6. There has, then, been a rapid decline in the rate of cell multiplication just in this period when differentiation is going on. This is, so far as I know, an entirely new line of research. The counting of a thousand cells is not to be done very rapidly ; it must be under- taken with patience, care, and requires time. It has not, I regret to say, been possible for me yet to ex- tend the number of these counts beyond those I have given you, but it is safe to say that in the yet more differentiated state, the number of cells in divi- sion is constantly lessened, and it is only a question of counting to determine the mitotic index accurately. That there is a further diminution beyond that which the mitotic indices I have demonstrated to you repre- sent is perfectly certain. I only regret that I am not able to give you exact numerical values. I wish very much that my time permitted me to branch off into certain topics intimately associated with the general theme we have been considering together on these successive evenings, but we can only allude to a few of these. The first collateral subject on which I wish to speak to you briefly is that which we call the law of genetic restriction} which ' C. S. Minot, Laboratory Text-book of Embryology (1903), p. 30. This law of genetic restriction had been foreshadowed by M. Nussbaum {Arch.f. microsk. Anal., xxvi., pp. 522, 524). He expresses well and ingeniously the change of progressive differentiation in Metazoan cells. His idea is that each cell is a THE FOUR LAWS OF AGE 223 means that after a cell has progressed and is differen- tiated a certain distance, its fate is by so much deter- mined. It may from that pass on, turn in one direction or another, always progressing, going onward in its cytomorphosis ; but the general direction has been prescribed, and the possibilities of that cell as it pro- gresses in its development become more and more restricted. For instance, the cells which are set apart to form the central nervous system after they are so set apart cannot form any other kind of tissue. ^ After the nervous system is separated in the progress of development from the rest of the body, its cells may become either nerve cells proper or supporting cells (neuroglia), which latter never acquire the nervous character proper, but serve to uphold and keep in place the true nervous elements. They represent the skeleton of the central nervous system. After the ^ " multiplum lebensfahiger nnd gestaltender Substanz." As the ovum can pro- duce two ova, it can produce two individuals. Ectoderm cells can produce more ectoderm, but not a whole new individual. > An unexpected exception to this statement has been discovered, which is, however, more apparent than real. In certain Amphibia it has been found that, if the lens of the eye is extirpated from a young larva, a new lens will be formed at the expense of the retina, which itself arises from an outgrowth of brain tissue. At the time the retinal lens is produced, however, the retinal cells are still in an undifferentiated state, and those retinal cells which have advanced to the stage of young differentiated elements cannot produce a lens. The normal lens is developed from the outer skin (epidermis) of the embryo. See A. Fischel, Anato7nische Hefte, xiv., p. i, (1900) and Archiv. f. Entwickelungs- ?)iech,, XV., p. i; G. Wolff, Archiv, f. Entwickelungsmeck., i., pp. 380- 390, and xii., pp. 307-351 ; W. H. Lewis, A?nericanyoiirnal of Anatomy, iii. 505-536, 1904. It is important to note that the retinal lens differs greatly in its cell structure from the normal lens, and is smaller, though resembling it in general form. 224 AGE, GROWTH, AND DEATH cells of the nervous system are separated into these two fundamental classes they cannot change. A cell form- ing a part of the supporting framework of the brain cannot become a nerve cell ; and a nerve cell cannot become a supporting cell. The destiny of them be- comes more and more fixed, their future possibili- ties more and more limited, as their cytomorphosis goes on. The law of genetic restriction has a very important bearing upon questions of disease. When disease occurs, the cells of the body offer to us two kinds of spectacles. Sometimes we see that the cells causing the diseased condition are more or less of the sort which naturally belong in the body ; that they are present where they do not belong, or they are present where they ought to be, but in excessive quantity. There is a kind of tumor which we call a bony tumor. It consists of bone cells such as are natur- ally present in the body, but that which makes this growth of bone a tumor is its abnormal dimensions, or perhaps its being altogether in the wrong place. The second sort of pathological alteration, which I had in mind, is that in which the cells really change their character. Now, the young cells are those which can change most ; in which the genetic restriction has least come into play ; and accordingly we find that a large number of dangerous, morbid growths, tumors, arise from cells of the young type, and these cells, having an extreme power of multiplication, grow rapidly, and they may assume a special character of THE FOUR LAWS OF AGE 225 their own ; their genetic restriction has not gone so far that all their possibilities of change in the way of differentiation have been fixed ; there is a certain range of possibilities still open to them, and they may turn in one direction or the other. Hence there may be pathological growths of a character not normally present in the body. It seems to me, so far as my knowledge of this subject enables me to judge, to be true that all such pathological growths depend upon the presence of comparatively young and undifferen- tiated cells beinor turned into a new direction. The problem of normal development and of abnormal structure is one and the same. Both the embryo- logist and the anatomist, on the one hand, and the pathologist and the clinician on the other, deal ever with these questions of differentiation, and practically with no others. All that occurs in the body is the result of various differentiations, and whether we call the state of that body normal or pathological matters little ; still the cause of it is the differentiation of the parts. The second of the collateral topics which I should like briefly to allude to is another branch of the study of senescence. The fact was first emphasised by the late Professor Alpheus Hyatt that in many animals there exist parts formed in an early stage and there- after never lost. The chambered nautilus is an animal of this kind. The innermost chamber represents the youngest shell of the nautilus, and as its age increases, it forms a new chamber in its shell, and so yet more 15 226 AGE, GROWTH, AND DEATH and more until the coil Is complete. When we examine a shell of that kind we see permanently before us the various stages, both young and old, as recorded in shell formation. And so too in the sea-urchin, and in many of the common shell-fish, we find the double record, of youth and old age, preserved permanently. This has made it possible for Professor Hyatt and for Professor Robert T. Jackson, who has adopted a similar guiding principle, to bring new light into the study of animal changes, and to attack the solution of problems which without the aid of this senescent in- terpretation, if I may so term it, would be utterly impossible. This is an enticing subject, and I wish I had both time and competency to dwell upon it. But it is aside, as you see, from the main inquiries with which we have been occupied, for our inquiries con- cern chiefly the effect of cell-change upon the proper- ties of the body, and the correlation of cell-change with aofe. A natural branch of our topic is, however, that of longevity, the duration of life,^ Concerning this, we have very little that is scientifically satisfactory that we can present. We know, of course, as a funda- mental principle, that every animal must live long enough to reproduce its kind. Did that not occur, the species would of course become extinct, and the mere fact that the species is existing proves, of course, * We are indebted to August Weissmann for raising the discussion of longevity to the level of science. His essay, Ueber die Dattcr des Lebcus (Jena, 1S82), is by far the best on the subject known to me, and includes numerous data on the longevity of animals. THE FOUR LAWS OF AGE 227 this simple fact — that life has lasted long enough for the parents to produce offspring. The consideration of this fact has led certain naturalists to the supposi- tion that reproduction is the cause of the termination of life ; but it is not, it seems to me, at all to be so interpreted. We know, in a general way, that large animals live longer than small ones. The elephant is longer lived than the horse, the horse than the mouse, the whale than the fish,^ the fish than the insect, and so on throuofh innumerable other instances. At first this seems a promising clue, but if we think a moment longer we recognise quickly the fact that a parrot, which is much smaller than a dog, may live one hundred years, whereas a dog is very old at twenty. There are insects which live for many years, like the seventeen-year locusts, and others which live but a single year or a fraction even of one year, and yet the long-lived and the short-lived may be of the same size. It is evident, therefore, that size is not in itself properly a measure of the length of life.2 Another supposition, which at first sounds very attractive, is that which explains the duration of life by the rate of wear, of the using up, of the wearing out, of the body. This theory has been particularly put forward by Professor Weissmann, who in his writings calls it the Abmitzungstheorie — the theory of the wearing out of the body. But the body does not really wear out » But there are some species of fish which outlive whales ; thus the European carp is said to live more than a century. ^ See Appendix No. IV, F. A. Lucas's letter. 228 AGE, GROWTH, AND DEATH in that sense. It goes on performing the functions for a long time, and after each function is performed the body is restored, and we do not find at death that the parts have worn out. But, as we have seen, we do find at death that there has been an extensive cytomorphosis, cell-change, and that the living ma- terial, after having acquired its differentiation, passes now in one part, now in another, then in a third, to a yet further stage, that of degeneration, and the result of degeneration, or atrophy, as the case may be, is that the living protoplasm loses its living quality and becomes dead material, and necessarily the functional activity ceases. We must, it seems to me, conclude that longevity, the duration of life, depends upon the rate of cytomorphosis. If that cytomorphosis is rapid, the fatal condition is reached soon, if it is slow, the fatal condition is postponed. And cytomorphosis in various species and kinds of animals must proceed at different rates and at different speeds at different ages. Birds grow up rapidly during their period of development ; the cell-change occurs at a high speed, far higher than that which occurs in man, probably, during his period of development. But after the bird has acquired its mature development, it goes on almost upon a level for a long time ; the bird which becomes mature in a single year may live for a hundred or even more. There can be during these hundred years but a very slow rate of change. But in a mammal, a dog or a cat, creatures of about the same bulk as some large birds, we find that the early development is THE FOUR LAWS OF AGE 229 at a slower rate. The mammals take a much longer period to pass through their infancy and reach their maturity, but after they have reached their maturity they do not sustain themselves so long. Their later cytomorphosis occurs at a higher speed than the bird's. This is a field of study which we can only recognise the existence of at present, and which needs to be explored before, to any general, or even to a special scientific, audience, any promising hypotheses can be presented. Definite conclusions are of course still more remote. Next as regards death. The body begins its de- velopment from a single cell, the number of cells rapidly increases, and they go on and on increasing through many years. Their whole succession we may appropriately call a cycle. Each of our bodies repre- sents a cell cycle. When we die, the cycle of cells gives out, and, as I have explained to you in a pre- vious lecture, the death which occurs at the end of the natural period of life is the death which comes from the breakingr down of some essential thingr — some essential group of members of this cell cycle ; and then the cycle itself collapses. But the death is the result of changes which have been going on through the successive generations of cells making up this cycle. There are unicellular organisms; these also die ; many of them, so far as we can now deter- mine, never have any natural death, but there are probably others in which natural death may occur. It is evident that the death of a unicellular organism is 230 AGE, GROWTH, AND DEATH comparable to the death of one cell in our own bodies. It is not properly comparable to the death of the whole body, to the ending-up of the cell cycle. August Weissmann was led to a series of erroneous notions concerning death by his failure to distinguish between the death of a cell and the death of a cycle of cells. Let him serve as a warning to us. Is there anything like a cell cycle among the lower organisms ? among the protozoa, as the lowest animals are called ? It has been maintained by a French investigator, by the name of Maupas, that such a cycle does exist, that even in these low organisms there is a cell which begins the development, and that gradually the loss in the power of cell multiplication goes on until the cycle gives out and has to be renewed by a rejuvenes- cent process, and this rejuvenating process he thinks he has found in the so-called conjugating act of these animals, in which there occurs a curious migration of the nucleus of one individual into the cell body of another. Whether he is right or not remains still to be determined. It means much that Professor G. N. Calkins, one of the world authorities on protozoa and easily the foremost American master of this branch of zoology, thinks that cyclical development rules the protozoa, each cycle ending with natural death. You will recognise, I hope, from what I have said, that we have now some kind of measure of what constitutes old and young. We can observe the difference in the proportion of protoplasm and nucleus, the increase or diminution, as the case may be, of one or the other. THE FOUR LAWS OF AGE 231 If it be true that there is among protozoa, among unicellular animals, anything comparable to the gradual decline in the growth power which occurs in us, we shall expect it to be revealed in the con- dition of the cells — to see in those cells which are old an increase in the proportion and in the differentiation of their protoplasm, and consequently a diminution in the relative amount of nucleus. That subject is now being investigated, and we shall probably know, within a few years at least, something positive in this direc- tion. At present we are reduced to posing our question. We must wait patiently for the answer. The scientific man has many occasions for patience. He has to make his investigations rather where he can than where he would like to. Certain thing-s are accessible to our instruments and methods of research at the present time, but other things are entirely hidden from us and inaccessible at the present. We are indeed, more perhaps than people in any other profession of life, the slaves of opportunity. We must do what we can in the way of research, not always that which we should like most to do. Per- haps a time will come when many of the questions connected with the problems of growing old, which we can now put, will be answered, because oppor- tunities which we have not now will exist then. Scientific research offers to its devotees some of the purest delights which life can bring. The investigator is a creator. Where there was nothing- he brines forth something. Out of the void and the dark, he 232 AGE, GROWTH, AND DEATH creates knowledge, and the knowledge which he gath- ers is not a precious thing for himself alone, but rather a treasure which by being shared grows ; if it is given away it loses nothing of its value to the first discoverer, but acquires a different value and a greater usefulness that it adds to the total resources of the world. The time will come, I hope, when it will be generally understood that the investigators and think- ers of the world are those upon whom the world chiefly depends. I should like, indeed, to live to a time when it will be universally recognised that the military man and the government-maker are types which have survived from a previous condition of civilisation, not ours ; and when they will no longer be looked upon as the heroes of mankind. In that future time those persons who have really created our civilisation will receive the acknowledgment which is their due. Let these thoughts dwell long in your meditation, because it is a serious problem in all our civilisation to-day how to secure due appreciation of the value of thought and how to encourage it. I believe every word spoken in support of that great recognition which is due to the power of thought is a good word and will help forward toward good results. In all that I have said, you will recognise that I have spoken constantly of the condition of the living material. If it is in the young state it has one set of capacities. If it is differentiated, it has, according to the nature of its differentiation, other kinds of capa- THE FOUR LAWS OF AGE 233 cities. We can follow the changing structure with the microscope. We can gain some knowledge of it by our present chemical methods. Fragmentary as that knowledge is, nevertheless, it sufifices to show to us that the condition of the living niate7''ial is essential and determines what the living inaterial can do. I should like to insist for a moment upon this conception, be- cause it is directly contrary to a conception of living material which has been widely prevalent in recent years, much defended and popularly presented on many different occasions. The other theory, the one to which I cannot subscribe, may perhaps be most conveniently designated by the term — the theory of life units. It is held by the defenders of this faith that the living substance contains particles, very small in size, to which the vital properties are especially attached. They look at a cell and find that it has water, or water containing a small amount of salts in solution, filling up spaces between the threads of pro- toplasm. Water is not alive. They see in the proto- plasm granules of one sort and another, in plants chlorophyll, in animals perhaps fat or some other material. That is not living substance, and so they go, striking out from their conception of the living material in the cell one after another of these com- ponent parts until they get down to something very small, which they regard as the life unit. I do not believe these life units exist. It seems to me that all these dead parts, as this theory terms them, are parts of the living cell. They are factors which enable the 234 AGE, GROWTH, AND DEATH functions of life to go on. Other conditions are also there, and to no one of them does the quality of life properly attach itself. Of life units there is an ap- palling array. The most estimable of them, in my opinion, are the life units which were hypothetically created by Charles Darwin in his theory of pangenesis. He assumed that there were small particles (gem- mules) thrown off from different portions of the body circulating throughout the body, gathering sometimes in the germ cells. These particles he assumed to take up the qualities of the different parts of the body from which they emanated, and by gathering together in immense numbers in the germ cells to accomplish the hereditary transmission. We know now that this theory is not necessary, that it is not the correct theory. But at the time that Darwin promulgated it, it was a perfectly sound, defensible theory, a theory which no one considering fairly the history of bio- logical knowledge ought to criticise unfavourably. It was a fine mental achievement, but I should like also to add that of all the many theories of life units, this of Darwin is the only one which seems to me intel- lectually entirely respectable. Of supposed structural life units there is a great variety. Besides the gem- mules of Darwin, there were the physiological units of Herbert Spencer. Professor Haeckel, the famous German writer, has structural life units of his own which he terms plastidules ; he gave his theory the charming alliterative title of perigenesis of the plasti- dules ; the rhythm of it must appeal to you all, though THE FOUR LAWS OF AGE 235 i the hypothesis had better be forgotten. Then came NageH, the great botanist, who spoke of the Idio- plasma-Theilchen. Then Weisner, also a botanist, who spoke of the plassomes. Our own Professor Whitman attributed to his life units certain other es- sential qualities and called them idiosomes. A German zoologist, Haacke, has called them gemmules. An- other German writer, a Leipzig anatomist, Altmann, calls them granuli. Now these different life units, of which I have read you briefly the names, are not identical according to these authors. Everybody else's life units are wrong, falsely conceived, and endued with qualities which they do not combine. Here is a curious assemblage of " doxies," and each writer is orthodox and all the others are heterodox ; and I find myself viewing them all from the standpoint of my "doxy," that of the structural quality of the living matter, and, therefore, interpreting every one of these conceptions as heterodox, not sound doctrine, but something to be rejected, condemned, and fought against. These theories of life units have filled up many books. Among the most ardent defenders of the faith in life units is Professor Weismann, whose theories of heredity many of you have heard discussed ; though I doubt if many of you, unless you recall what I said previously, are aware of the fact that the es- sential part of Weismann's doctrine was the adoption of the theory of germinal continuity originated by Professor Nussbaum, whose name by a strange in- justice has been too seldom heard in these discussions* 236 AGE, GROWTH, AND DEATH Weismann has gone much farther in the elaboration of the conception of hfe units than any of the other writers. He thinks the smallest of the life units are biophores. A group of biophores brought together constitutes another order of life units which he calls determinants; the determinants are again grouped and form ids ; and the ids are again grouped and form idants. If you want to accept any theory of life units, I advise you to accept that of Weismann, for it offers a large range for the imagination, and has a much more formidable number of terms than any other, I want to pass now to an utterly different line of study, the question of psychological development. If it be true that the development is most rapid at first, slower later, we should expect to find proof of that rate in the progress of mental development. In other words, we should expect to find that the baby de- veloped faster than the child mentally, that the child developed faster than the young man, and the young man faster than the old. And do you not all instinc- tively feel immediately that the general assertion is true? In order, however, that you may more fully appreciate what I believe to be the fact of mental development going on with diminishing rapidity, I should like to picture to you briefly some of the things which the child achieves during the first year of its life.^ When the child is born, it is undoubtedly 1 I am indebted to Dr. Benjamin Rand of Harvard University for guidance to the literature upon the subject of the mental development of children. The account in the text is the result of reworking the recorded data, so as to elucidate the relation of the child's mental progress to its age, none of the THE FOUR LAWS OF AGE 237 supplied with a series of the indispensable physiologi- cal functions, all those which are concerned with the taking in and utilising of food. The organs of diges- tion, assimilation, circulation, and excretion are all functionally active at birth. The sense organs are also able to work. Sense of taste and of smell are doubt- fully present. It is maintained that they are already active, but they do not show themselves except in re- sponse to very strong stimulation. Almost the only additional faculty which the child has is that of mo- tion, but the motions of the new-born baby are per- fectly irregular, accidental, purposeless, except the motions which are connected with the function of sucking, upon which the child depends for its nourish- ment. The instinct of sucking, the baby does have at birth. It might be described as almost the only equipment beyond the mere physiological working of its various organs. But at one month we find that this uninformed baby has made a series of important authorities I have consulted having presented the matter with special reference to the age rate. I have drawn chiefly from the following publications : Compayre "La psychologie de Yeniant," Revttepkilosophique, vi., 1878, 464- 481. Ch. Darwin, "Biographical Sketch of an Infant," Mind, ii., 1877, 285-294. Louise Hogan, Study of a Child, New York, 1898. Kussmaul, Seeletileben des neugeborenen Menschen, i8g6. Kathleen Moore, "Mental Development of a Child," Psychol Review, Sup- plement, Oct., 1896. Oppenheim, The Development of a Child, New York, 1898. Wm. Preyer, The Mind of the Child. Translated by H. W. Brown. 2 vols. One of the most important and suggestive works on the subject. M. W. Shinn, The Biography of a Baby, Boston, 1900. An excellent book, both authoritative and readable. Amy E. Tanner, The Child, New York, 1904. 238 AGE, GROWTH, AND DEATH discoveries. It has learned that there are sensations, that they are interesting ; it will attend to them. You all know how a baby of one month will stare ; the eyes will be fastened upon some brig-ht and interest- ing object. At the end of a month the baby shows evidences of having ideas and bringing them into correlation, — association, as one more correctly ex- presses it, — because already after one month, when held in the proper position in the arms, it shows that it expects to be fed. There is, then, already evidence and trace of memory. At two months much more has been achieved. The baby evidently learns to expect things. It expects to be fed at certain times ; it has made the great discovery of the existence of time. And it has made the discovery of the existence of space, for it will follow to some extent the bright light ; it will hold its head in a certain position to catch a sound apparently from one side ; or to see in a certain direction. The sense of space and time in the baby's mind is, of course, very imperfect, doubt- less, at this time, but those two non-stuff realities about which the metaphysicians discuss so much, the two realities of existence which are not material, the baby at this time has discovered. Perhaps, had some great and wonderfully endowed person existed who preserved the memory of his own psychological his- tory, of his development during babyhood, we should have been spared the gigantic efforts of the meta- physicians to explain how the notions of space and time arose. Without knowing how, the baby has ac- THE FOUR LAWS OF AGE 239 quired them, and has already become a rudimentary metaphysician. We see, also, at the end of the third month, that the baby has made another remarkable discovery. It has found not merely that its muscles will contract and jerk and throw its parts about, which surely was earlier a great delight to it; but that the muscles can contract in such a way that the move- ment will be directed ; there is a co-ordination of the muscular movements. I should like to read to you just these three or four lines from Miss Shinn, who has given perhaps the best story of the development of a baby which has yet been written. This is not merely my opinion, but also the opinion of my psycho- logical colleagues at Cambridge whom I consulted before venturing to express the idea before you, and I find that they take the view that Miss Shinn's book, which is charmingly written, is really done with such precision and understanding of the psychological pro- blems involved that it may fairly be called the best of the books treating of the mental development of a baby. Miss Shinn says, referring to the condition of the child at the end of two months — "Such is the mere life of vegetation the baby lived during the first two months ; no grown person ever experienced such an expansion of life — such a progress from power to power in that length of time." She is not thinking of senescence, as we have been thinking of it, but she makes precisely the assertion, which seems to me to be true, that the baby in two months has accomplished an amount of development which no adult is capable 240 AGE, GROWTH, AND DEATH of. And now at three months we find another great discovery is made by the baby, that it is possible to bring- the sensations which it receives into combina- tion with the movements which it makes. It learns to co-ordinate its sensory impressions and its motor responses. We hardly realise what a great role this adjustment, between what our muscles can do and what our senses tell us, plays in our daily life. It is the fundamental thing in all our daily actions, and though by habit we perform it almost unconsciously, it is a thing most difficult to learn. Yet the baby has acquired the art, though he only gradually gets to be perfect in it. Again we see, at the end of the fourth month, that the baby begins to show some idea of an- other great principle — the idea that it can do some- thing. It shows evidence of having purpose in what it does. Its movements are no longer purely acci- dental. At four months we find yet another equally astonishinof addition to the achievements of this mar- vellous baby. He makes the amazing discovery that the two sides of an object are not separate things, but are parts of the same. When a face, for instance, disappears by a person's turning around, that face, to a baby of one month, probably simply vanishes, ceases to exist : but the baby at four months realises that the face and the back of the head belong to the same object. He has acquired the idea of objects existing in the world around him. That is an enormous achievement, for this little baby has no instructor; he is finding out these things by his own unaided efforts. THE FOUR LAWS OF AGE 241 Then at five months begins the age of handhng when the baby feels of everything. It feels urgently of all the objects which it can get hold of and perhaps most of all of its own body. It is finding that it can touch its various own parts and that when its hands and parts of Its own body come in contact it has the double sensations, and learns to bring them together and thereby is manufacturing in its consciousness the con- ception of the ego, personal, individual existence, an- other great metaphysical notion. Descartes has said, ''Cogito, ergo sum' — " I think, therefore I am." The baby, if he had written in Descartes's place, would have said, " I feel, therefore I am." The first five months constitute the first period of the baby's de- velopment Its powers are formed, and the founda- tions of knowledge have been laid. The second period is a period of amazing research, constant, un- interrupted, untiring; renewed the instant the baby wakes up, and kept up until sleep again overtakes It. In the six months' baby we find already the notion of cause and effect. You see he Is dealing mostly In metaphysical things, getting the fundamental con- cepts. That there Is such an idea as cause and effect in the baby's mind is clearly shown by the progress of its adaptive intelligence. It evidently has now distinct purposes of its own. It shows clearly at this age also another thing which plays a constant and Important r6le in our daily life. It has the consciousness of the possibilities of human intercourse ; It wants human companionship. And with that the baby's equipment 16 242 AGE, GROWTH, AND DEATH to start upon life is pretty well established. It has discovered the material universe in which it lives, the succession of time, the nature of space, cause and effect, its own existence, its ego and its relationship with other individuals of its own species. Do we get at any time in our life much beyond this ? Not very much ; we always use these things, which we learn in the first six months, as the foundation of all our thought. By eight months, baby is upon the full career of experiment and observation. Everything with which the baby comes in contact interests him. He looks at it, he seizes hold of it, tries to pull it to pieces, studies its texture, its tensile strength, and every other quality it possesses. Not satisfied with that, he will turn and apply his tongue to it, putting it in his mouth for the purpose of finding out if it has any taste. In doing this, hour after hour, with un- ceasing zeal, never interrupted diligence, he rapidly gets acquainted with the world in which he is placed. At the same time he is making further experiments with his own body. He begins to tumble about ; perhaps learns that it is possible to get from one place to another by rolling or creeping, and slowly he dis- covers the possibility of locomotion, which you know by the end of the year will have so far perfected itself that usually at twelve months the baby can walk. During this period of from five months to twelve the baby is engaged upon a career of original research, unaided much by anybody else, getting doubtless a little help and, of course, a great deal of protection, THE FOUR LAWS OF AGE 243 but really working chiefly by himself. How wonder- ful it all is ! Is any one of us capable of beginning at the moment we wake to carry on a new line of thought, a new series of studies, and to keep it up full swing, with unabated pace, all day long till we drop asleep ? Every baby does that every day. When we turn to the child who goes to school, be- hold how much that child has lost. It has difficulties with learning the alphabet. 1 1 struggles slowly through the Latin grammar, painfully with the subject of geometry, and the older it gets the more difficult becomes the achievement of its study. The power of rapid learning, which the baby has, is clearly already lessened. The introduction of athletics affords a striking illus- tration of the decline of the learning power with the progressing years. When golf first came in it was con- sidered an excellent game for the middle-aged; and you have all watched the middle-aged man play. He was so awkward, he could not do it. Day after day the man of forty, fifty, or even older, would go to the golf field, hoping each time to acquire a sure stroke, but never really acquiring it. The young man learned better, but the good golf players are those who begin as children, twelve and fourteen years of age, and in a few months become as expert and sure as their fathers wished to become, but could not. In bicycling it was the same. Eight lessons was considered the number necessary to teach the intelligent adult to ride a wheel. Three for a child of eiorht. And an indefinite 244 AGE, GROWTH, AND DEATH number of lessons, ending in failure, for a person at seventy. It would have been scientifically interesting to have kept an exact record of the period of time which it took at each age to learn bicycling, but I think enough has been said to convince you that if we could acquire such a measure of psychological develop- ment as would enable us to express its rate in figures, we should be able to construct a curve like the curve which I showed you in the third lecture illustrating the decline in the rate of growth, and we should see that during the early years of life the decline in the power of learning was extremely rapid, during childhood less rapid, during old age very slow. But the great part of the decline would occur during early years. Here we see the principle of stability, in maturity, which we see also illustrated in structure and growth. The mind acquires its development; it retains that de- velopment in the adult a long time. But surely there comes a period when the exercise of the mind is dififi- cult. It requires a great effort to do something new and unaccustomed. A sense of fatigue overwhelms us. I believe that this principle of psychological de- velopment, paralleling the career of physical develop- ment, needs to be more considered in arranging our educational plans. For if it be true that the decline in the power of learning is most rapid at first, it is evident that we want to make as much use of the early years as possible — that the tendency, for instance, which has existed in many of our universities, to post- pone the period of entrance into college Is biologically THE FOUR LAWS OF AGE 245 an erroneous tendency. It would be better to have the young man get to college earlier, graduate earlier, get into practical life or into the professional schools earlier, while the power of learning is greater. Do we not see, in fact, that the new ideas are indeed for the most part the ideas of young people ? As Dr. Osier, in that much-discussed remark of his, has said, the man of forty years is seldom the productive man. Dr. Osier also mentioned the amiable suororestion of Trollope in regard to men of sixty, which has been so extremely misrepresented in the newspaper discus- sions throughout the country, causing biologists much amusement. But I think that Dr. Osier probably took a far too amiable view of mankind, and that in reality the period when the learning power Is nearly obliter- ated is reached in most individuals very much earlier. Permit me to read to you a quotation from a lecture which I delivered last year (1906) before the Harvey Society: " It msiy be true that that age (40) marks in intellectual men usually a transition or the point where the accumulated losses which have been occurring from birth on reveal their effects clearly, but in the great majority of men comparative mental fixity surely occurs at a much earlier period. If you will allow me to wander for a moment from the strict discussion of our immediate theme, I should like to refer to what may be called the theory of perma- nent mental fatigue. The organic changes which go on in the nervous system diminish its pliability and there comes a time when the individual finds it exceedingly difficult to bring his mind into any unaccustomed form of activity. How completely we are mastered by this difficulty is often hidden, I believe, from our 246 AGE, GROWTH, AND DEATH recognition and from that of our friends, because we have acquired certain habits of activity which we are able to keep up, but we are not able without ever-increasing difficulty to turn to new forms of mental activity, or in other words, to learn new things. When we grow old we may still continue to do well the kind of thing which we have learned to do, whether it be paying out bills at a bank or paying out a particular set of scientific ideas to a class of students. If we try to overstep the limits of our acquired expertness we find that we are held up by this sense of permanent mental fatigue. Usually this condition comes about gradually, but I have known, as I presume you all have, several cases in which it has appeared suddenly, where a man who up to a certain time was fond of mental exertion suddenly ceased to be mentally active. We have probable illustrations of this in the careers of well-known scientific men. I think the theory of permanent mental fatigue, in connection with the theory of gradual decline which we are considering this evening, could be usefully devel- oped and might well be utilised by the psychologists in their studies." As in every study of biological facts, there is in the study of senescent mental stability the principle of vari- ation to be kept in mind. Men are not alike. The great majority of men lose the power of learning, doubtless some more and some less, we will say, at twenty-five years. Few men after twenty-five are able to learn much. They who cannot, become day-labour- ers, mechanics, clerks of a mechanical order. Others probably can go on somewhat longer, and obtain higher positions; and there are men who, with extreme varia^ tions in endowment, preserve the power of active and original thought far on into life. These of course are the exceptional men, the great men. THE FOUR LAWS OF AGE 247 We have lingered so long together studying phe- nomena of growth, that it is natural to allude to one more, which is as singular as it is interesting, namely, the increase in size of Americans. It was first demon- strated by Dr. Benjamin A. Gould in his volume of statistics derived from the records of the Sanitary Commission — a volume which still remains the classic and model of anthropometric research. Any one, how- ever, can observe that the younger generation of to-day tends conspicuously to surpass its parents in stature and physical development. How to explain the remarkable improvement we do not know. Our discovery of the fact that the very earliest growth is so enormously rapid, makes that earliest period especially important. If the initial growth can be favoured, a better subsequent development presumably would re- sult. In brief, I find myself led to the hypothesis that the better health of the mothers secures improved nourishment in the early stages of the offspring, and that the maternal vigour is at least one important immediate cause of the physical betterment of the children. Much is said about the degeneracy of the American race, but the contrary is true — the Amer- ican race surpasses its European congeners in physical development. You will naturally wish to ask, before I close the series of lectures, two questions. One, how can rejuvenation be improved ? the other, how can senescence be de- layed ? These questions will strike every one as very practical. But the first, I fear, is not an immediately 248 AGE, GROWTH, AND DEATH practical question, but rather of scientific interest, for we must admit that the production of young individ- uals is, on the whole, very well accomplished and much to our satisfaction. But in regard to growing old, in regard to senescence, the matter is very different. There we should, indeed, like to have some principle given to us which would retard the rate of senescence and leave us for a longer period the enjoyment of our mature faculties. I can, as you have readily surmised by what I have said to you, present to you no new rule by which this can be accomplished, but I can venture to suggest to you that in the future deeper insight into these mysteries probably awaits us, and that there may indeed come a time when we can somewhat reg- ulate these matters. If it be true that the growing old depends upon the increase of the protoplasm, and the proportional diminution of the nucleus, we can perhaps in the future find some means by which the activity of the nuclei can be increased and the younger system of organisation thereby prolonged. That is only a dream of the possible future. It would not be safe even to call it a prophecy. But stranger things and more unexpected have happened, and perhaps this will also. I do not wish to close without a few words of warn- ing explanation. The views which I have presented before you in this series of lectures I am personally chiefly responsible for. Science consists in the dis- coveries made by individuals, afterwards confirmed and correlated by others, so that they lose their personal THE FOUR LAWS OF AGE .049 character. You ought to know that the interpreta- tions which I have offered you are still largely in the personal stage. Whether my colleagues will think that the body of conceptions which I have presented are fully justified or not, I cannot venture to say. I have to thank you much, because between the lecturer and his audience there is established a personal relation, and I feel very much the compliment of your presence throughout this series of lectures, and of the very courteous attention which you have given me. To recapitulate — for we have now arrived at the end of our hour — it must be said first that all of the conclus- ions presented are based upon the laws of cytomor- phosis, in other words, of the change in structure which occurs not only in a single cell, but progressively in successive generations of cells. We can formulate the following laws of cytomorphosis: Fii^st, cytomorphosis begins with an undifferenti- ated cell. Second, cytomorphosis is always in one direction, through progressive differentiation and degeneration towards the death of the cells. Third, cytomorphosis A^aries in degree characteris- tically for each tissue (hence in the adult higher ani- mals nearly all stages of cytomorphosis may co-exist). We may add that reversed cytomorphosis is not known to occur, or, in other words, differentiated ma- terial cannot be restored to the undifferentiated con- dition. Finally, if my arguments before be correct, we rnay 2 50 AGE, GROWTH, AND DEATH say that we have estabHshed the following four laws of age : First, rejuvenation depends on the increase of the nuclei. Second, senescence depends on the increase of the protoplasm, and on the differentiation of the cells. Third, the rate of growth depends on the degree of senescence. Fourth, senescence is at its maximum in the very- young stages, and the rate of senescence diminishes with age. As the corollary from these, we have this — natural death is the consequence of cellular differentiation. APPENDICES 251 APPENDIX I. GROWTH OF RABBITS. 'T'HE data which I have collected concerning the growth of ^ rabbits have not been published hitherto, and are therefore printed here. It is from the average of the percentage incre- ments that Figures 35 and 36 were constructed. There are certain precautions in making weighings, not only of rabbits but also of other animals, which were found necessary. As soon as a litter was born and the amniotic fluid dried off from the fur of the young, each individual was weighed, the sex noted, and an exact description of all the markings, which do not alter after birth, written down. The litter was numbered, and the date of birth and the parentage, or at least the maternal par- entage, recorded. To identify the rabbits they were marked with spots of nitrate of stiver. It may be mentioned in passing that the Guinea-pigs, of which there was a large number raised, can usually be indi- vidually identified by their natural markings. I found it a great convenience to give mnemonic names to all the pigs of which I. followed the growth, so that the name would sug- gest the appearance of the individual pig. For the most part the names referred directly to the marking, for instance, " Brown rump," "Saddle back," "Snout," etc., — but often the allusion was more remote, as for instance, "Hypocrite," whose head, seen from one side, appeared entirely black, from the other, en- tirely white. The record having been started, the next thing was to enter in a diary all the dates during the remainder of the year upon which the litter in question was to be weighed.' The plan adopted after a little experience was to weigh each in- dividual every day up to 40 days, then every fifth day up to 215 ' The apparatus devised for calculating the required dates mechanically is described in Appendix VI. 253 254 AGE, GROWTH, AND DEATH days, and then after every thirtieth day, and to avoid accidental variations, also five days before and five days after each thirtieth day : for instance, the months being assumed at 30 days, the ani- mals would be weighed for the eighth month at 240, also at 235 and 245 days, and the next set for nine months, 265, 270, and 275, and so on to the end of the second year after birth, at which age the observations were stopped. Of no individual have I an abso- lutely complete series of weights, but of a good many the series are nearly complete. A very few of my animals died from disease. GROWTH OF RABBITS. A, MALES Total Increase Average Daily Av. Daily Age Days Weight Grams Obs. Average Over Last Measurement Daily Increase Per Cent. Increase Per Cent. Increase 201.3 4 50.3 I 238.9 4 59-7 9-4 9.4 18.5 1 2 272.6 4 68.1 8.4 8.4 14. 1 3 344-9 4 86.2 18. 1 18. 1 26.6 y 17.6 4 402.3 4 100.6 14-4 14.4 16.7 12.3 J 5 452.2 4 113.0 12.4 12.4 6 287.0 2 143-5 30.5 30.5 26.9^ 7 622.5 4 155-6 12. 1 12. 1 8.4 8 708.1 4 177.0 21.4 21.4 13.8 V 13-5 9 786.6 4 196.6 19.6 19.6 II. I 10 844.6 4 2X1. 1 14.5 14-5 7-4J II 922.0 4 230.5 19.4 19.4 9.2 1 12 993-2 4 248.3 17.8 17-8 7.7 13 683.0 2 341-5 93-2 93-2 37-5 } 15.6 14 1121.2 4 280.3 —61.2 — 61.2 —17.9 41.6 J 15 794.0 2 397.0 116. 7 116. 7 16 1265.0 4 316.2 —80.8 —80.8 — 20. 4 ^ 17 1356.0 4 339.0 22.8 22.8 7.2 18 922.0 2 461.0 122.0 122.0 36.0 V 10. T 19 1479-5 4 369-9 —91. 1 -91. 1 —19.8 20 1090 2 545-0 175-I 175. 1 47.3. 21 1627 4 406.7 -■38-3 —138.3 -25.4I 22 1122 2 561.0 154.3 154-3 37-9 23 1798 4 449-5 —III. 5 —III. 5 —19.9 V 6.6 24 1202 2 601.0 151-5 151-5 33-7 25 642 I 642.0 41.0 41.0 6.8j 26 1401 3 467.0 — 175-0 —175.0 —27-3"^ 27 1297 2 648.5 181. 5 181. 5 38.9 28 2215 4 553-7 -94-8 —94.8 — 14.6 V 5-3 29 1410 2 705-0 151. 3 151-3 27.3 30 1439 2 719-5 14.5 14.5 2.1 J APPENDIX I 255 •GROWTH OF RABBITS. A, M.M.^S— {Continued) Total Average Increase Over Last Measurement Average Daily Increase Daily Per Cent. Increase Age Days Weight Grams Obs. Av. Daily Per Cent. Increase 31 2502 4 625.5 —94.0 —94.0 — 13.0 32 1530 2 765.0 139-5 139-5 22.3 33 1564 2 7S2.O 17.0 17.0 2.2 > 3-1 34 1575 2 787-5 5-5 5.5 -7 35 1627 2 813.5 26.0 26.0 3-3J 36 1683 2 841.5 28.0 28.0 3.4 ] 37 2914 4 72S.5 — 113.0 — 113. — 13.4 33 1830 2 915.0 186,5 186.5 25.6 >• 5-5 39 1842 2 921.0 6.0 6.0 .7 40 3108 4 777-0 —144.0 —144.0 -I5-6J 45 3304 4 826.0 49.0 9.8 1.3 1 50 2071 2 I035-5 209.5 41.9 5.1 55 3881 4 970.2 -65.3 —13. 1 -1.3 \ 1.6 60 4167 4 1041.7 71-5 14.3 1-5 65 4465 4 1116.2 74.5 14-9 1.4J 70 4969 4 1242.2 126.0 25.2 2-3 ) 75 5519 4 1379-7 137-5 27-5 ""■Iy I.O 80 4013 3 1337-7 — 42.0 -8.4 -.b[ 85 2690 2 I345-0 7.3 1.5 .1 } 90 95 3120 2 1560.0 215.0 21.5 1.6) 100 3195 2 1597-5 37-5 7-5 ■n no 3555 2 1777-5 180.0 18.0 '•o\ I.O 120 3836 2 1918.0 140.5 14.0 .8 ; 150 4268 2 2134.0 216.0 7-2 A 165 4517 2 225S.5 124.5 8-3 -4 180 4570 2 2285.0 26.5 1.8 .1 > .3 195 4812 2 2406.0 121.0 8.1 .4 210 4954' 2 2477.0 71.0 4-7 .2^ Months 8 5052 2 2526.0 49.0 1.6 .071 9 4812 2 2406.0 — 120.0 —4.0 -1-3 [ —-4 10 4795 2 2397.5 -8.5 —•3 —.01 ) 256 AGE, GROWTH, AND DEATH GROWTH OF RABBITS. B, FEMALES, NOT LITTERING WHILE YOUNG Total 1 Average Increase Over Last Average Daily Daily Per Cent. Av. Daily Age Per Cent. Days Weight Grams Obs. Measurement Increase Increase Increase 242.8 5 486 I 275-9 5 55-2 6.6 6.6 13-6^ 2 310-3 5 62.1 6.9 6.9 12-5 3 391-5 5 78-3 16.2 16.2 26.1 V x6.o 4 431-7 5 86.3 8.0 8.0 10.2 5 507.2 5 IOI.4 15.1 15-I 17-5 J 6 252.0 2 126.0 24.6 24.6 24-2 ^ 4-4 7 657.5 5 131-5 5-5 5-5 8 746.6 5 149-3 17.8 17.8 13-5 V 11.4 9 806.5 5 161. 3 12.0 12.0 8.0 10 866.8 5 173-4 12. 1 12. 1 7-1 , II 922.7 5 184.5 II. I II. I 6.4 " 12 1012.2 5 202.4 17.9 17.9 9-7 13 576.0 2 288.0 85.6 85.6 42.3 > 15.3 14 1236.5 5 247-3 —40.7 —40.7 —14. 1 15 653-0 2 326.5 79-2 79-2 32.0 16 1257.0 5 251-4 —75-1 —75-1 —23.0 17 1314.0 5 262.8 II. 4 11.4 4-5 18 783.0 2 391.5 128.7 128.7 48.9 > 10.5 19 142 1 5 284.2 —107.3 —107.3 —27.4 20 850 2 425-0 140.8 140.8 49-5 . 21 1612 5 322.4 — 102.6 — 102.6 -24.1 1 22 923 2 461.5 139- 1 139-I 43-1 23 1785 5 357-0 —104.5 —104.5 —22.6 > 8.4 24 992 2 496.0 139.0 139.0 38.9 25 529 I 529-0 33-0 33-0 6-7 j 26 1507 4 376-7 —152.3 —152.3 —28.8 s 27 1098 2 549 -o 172.3 172.3 45-7 28 2251 5 450.2 —98.8 -98. 8 —18.0 > 6.8 29 1203 2 601.5 151-3 151-3 33-6 30 1222 2 611. 9-5 9-5 1.6 _ 31 2570 5 514-0 —97.0 —97-0 —15-9^ 32 1313 2 656.5 142.5 142.5 27.7 33 2670 5 5340 — 122.5 — 122.5 —18.7 . 4.7 34 1367 2 683-5 149-5 149-5 28.0 35 1398 2 699.0 15-5 15-5 2.3, 36 1461 2 730.5 31-5 31.5 4-5 \ 37 3073 5 614.6 -115-9 — "5-9 —15.9 38 1621 2 810.5 195-9 195-9 31-9 > .3 39 1606 2 803.0 —7.5 —7-5 —-9 40 3160 5 632.0 — 171. — 171. —21.3 45 3522 5 704.4 72-4 14-5 2.3 50 1872 2 936.0 231.6 46-3 66 55 4039 5 807.8 —128.2 —25 6 —2.7 2.4 60 4452 5 890.4 82.6 16.5 2.0 65 49-8 5 980.4 go.o 18.0 2.0 _ APPENDIX I 257 GROWTH OF RABBITS. B, FEMALES NOT LITTERING WHILE YO\j:sG— {Continued) Age Days Total Average Increase Over Last Measurement. Average Daily Increase Daily Per Cent. Increase Av. Daily Weight Grams Obs. Per Cent. Increase 70 5286 5 1057.2 76.8 154 1.6 "] 75 5668 5 I133.6 76.4 15-3 1.4 80 5964 5 II92.8 59-2 II. 8 I.O ]■ 1 .0 85 6362 5 1272.4 79.6 15.9 1-3 —0.1 J . 90 2528 2 1264.0 -8.4 —1.7 95 5839 4 1459- 7 195.7 39-1 ■■■! .9 ( 100 4626 3 1542.0 82.3 16.5 1.6 no 5055 3 1685.0 143.0 14-3 320 5494 3 1831-3 146.3 14.6 .9 J l^iO 609+ 3 2031.3 200.0 6.7 •4l .6 165 66S2 3 2227.3 196,0 I3-I iSo 7134 3 237S.0 150.7 10.0 •5 } .4 195 6934 3 2311.3 —66.7 —4-4 .2 .6 J 210 7597 3 2532.3 221.0 14-7 Months 8 5504 2 2752.0 219.7 7-3 •3 ) 9 5694 2 2b47.o 95-0 3.2 -A .1 10 5300 2 2650.0 —197.0 —6.6 APPENDIX II, GROWTH OF CHICKENS. T^HE data which I have collected concerning the growth of * chickens have not been published hitherto, and are there- fore printed here. It was from the percentage increments of these tables that Figures 33 and 34 were constructed. GROWTH OF CHICKENS. A, MALES Age Days Total Average Increase Over Last Measurement Average Daily Increase Daily Per Cent. Increase Av. Daily Weight Obs. Per Cent. Increase Grams I 93 2 46.5 2 92 2 46.0 — ■5 —•5 — I.I'^ 3 95 2 47-5 1-5 1-5 3.3 I 3-9 4 103 2 51-5 4.0 4.0 8-4 I 4-9J 5 108 2 54.0 2.5 2.5 6 120 2 60.0 6.0 6.0 II. i'^ 7 137 2 68.5 8.5 8-5 14.2 8 139 2 69.5 I.O 1.0 1.5 y 9.0 9 146 2 73-0 3-5 3-5 5.2 10 165 2 82.5 9-5 9-5 I3-0 J ir 180 2 go.o 7-5 7-5 9.0 12 187 2 93-5 3-5 3-5 3-9 13 189 2 94-5 1.0 1.0 I.I > 6.0 14 207 2 I03-5 9.0 9.0 9-5 15 220 2 IIO.O 6.5 6.5 6-3J 16 255 2 127-5 17.5 17-5 15-9^ 17 248 2 124.0 —3-5 —3-5 —2.7 iS 26S 2 134.0 lO.O 10,0 8.1 [ 6.5 19 288 2 144.0 10. 10. 7.5 20 298 2 149.0 5-0 5-0 3-5J 21 316 2 158.0 9.0 9.0 6.0 ^ 22 320 2 160.0 2.0 2.0 1-3 5-1 23 346 2 1730 13.0 13.0 8.1 ) 24 25 26 27 399 2 199-5 26.5 6.6 3.8] 4.8 [ 28 418 2 209.0 9-5 9-5 3-7 29 422 2 211. 2.0 2.0 .9 r 5-2J 30 444 2 222.0 II. II. 258 APPENDIX II 259 GROWTH OF CHICKENS. A, UKLY.S— {Continued) Age Total Average Increase Over Last Average Daily Daily Per Cent. Av. Daily Days Weight _ Grams Per Cent. Obs Measurement Increase Increase Increase 31 494 2 247.0 25.0 25.0 "■3l 32 524 2 262.0 15-0 15.0 6.1 33 533 2 266.5 4.5 4.5 1.7 > 5-2 34 564 2 282.0 15.5 15.5 5-8 35 570 2 285.0 3-0 3.0 i.i^ 36 600 2 300.0 15-0 15.0 5-3^ i.o 37 606 2 303.0 3.0 3.0 38 661 2 330.5 27.5 27.5 9.1 > 4.2 39 662 2 331.0 ■5 •5 .1 40 700 2 350.0 19.0 19.0 5-7. 42 737 2 368.5 18.5 9.2 2.6^ 44 788 2 394.0 25.5 12.7 3-4 46 815 2 407.5 13 5 6.7 .8 > 2.2 48 849 2 424.5 17.0 8.5 2.1 50 881 2 440.5 16.0 8.0 1.9^ 52 926 2 463.0 22.5 II. 2.5 ' 54 984 2 492.0 29.0 14.5 3.1 56 v 2.7 58 60 1127 2 563.5 71.5 II. 9 2.4 j 62 1194 2 597.0 33-5 16.7 2.9 \ 64 1182 2 591.0 ~6.o — 3.0 — .5 66 1297 2 648.5 57-5 28.7 4.8 V 2.8 68 1318 2 659.0 10.5 5.2 .8 70 1400 2 7ou,o 41.0 20.5 3.1 J 72 74 1552 2 776.0 76.0 19.0 2.7 1 76 / 78 \ 2.1 80 1692 2 846.0 70.0 II.7 1.5 ) 82 i'S53 2 926.5 80.5 40.2 4.7 1 86 1974 2 987.0 60.5 15. 1 1.6 90 2056 2 1028.0 41.0 10.2 1.0 V 94 2.3 98 2408 2 1204.0 176.0 22.0 2.1 j 102 2705 2 1352.5 14S.5 37-1 " [ 106 2783 2 1391.5 39-0 9-7 1.5 no 2869 2 1434.5 43-0 10.7 .8 S 120 3185 2 1592.5 158.0 15.8 I.I ■^ 125 3450 2 1725.0 132.5 26.5 1.7 130 3452 2 1726.0 I.O .2 .1 V 1.0 13s 3636 2 1818.0 92.0 18.4 I.I 140 3840 2 1920.0 102.0 20.4 I.I J 192 4897 2 2^48.5 528.5 10.2 •5 1 197 5025 2 2512.5 64.0 12.8 •5 - -3 202 4965 2 2482.5 — 30.0 —6.0 -.2 j 335 5552 2 2776.0 293-5 2.2 .09 \ .02 )■ 341 5559 2 2779-5 3-5 .6 .1 351 5475 2 2737-5 —42.0 —4.2 —.1 3 26o AGE, GROWTH, AND DEATH GROWTH OF CHICKENS. B, FEMALES Total Increase Average Daily Age Av. Daily Days Weight Average Over Last Daily Per Cent. Per Cent. Grams Obs. Measurement Increase Increase Increase 39 I 39 I 326 8 40.7 2 321 8 40.1 —.6 —.6 —1-5 ) 3 330 8 41.2 I.I I.I 2.7 f 4 352 8 44.0 2.8 2.8 6.8 r 4.2 5 383 8 47-9 3-9 3.9 8.9 ) 6 419 8 52.4 4 5 4.5 9-4 1 7 468 8 58.5 6.1 6.1 II. 6 8 475 8 59-4 •9 ■9 1-5 } 8.6 9 504 8 63.0 3.6 3-6 6.1 lO 577 8 72.1 9-1 9.1 14.4 j II 610 8 76.2 4.1 4.1 5.7 ^ 3-8 12 633 8 79.1 2.9 2.9 13 668 8 83.5 4-4 4.4 5.6 } 5-8 14 710 8 88.7 5-2 5-2 6.2 15 764 S 95-5 6.8 6.8 7.7 J i6 880 8 IIO.O 14-5 14-5 15-2 ^ 17 876 8 109.5 —.5 —•5 —•5 i8 938 8 117. 2 7-7 7-7 7.0 } 7.1 19 995 8 124.4 7.2 7.2 6.1 20 1071 8 133-9 9-5 9-5 7.6 j 21 1116 8 139-5 5-6 5-6 4.2 ) 22 1139 8 142.4 2.9 2-9 2.1 I 5.0 23 1082 7 154.6 12.2 12.2 8.6 ) 24 25 26 144 I 144.0 — 10.6 —3-5 —2.3 1 27 1356 8 169.5 25-5 25-5 17-7 28 1416 8 177.0 7-5 7.5 4-4 } 5-4 29 1448 8 181. 4.0 4.0 2.3 4.9 j 30 1519 8 189.9 8.9 8.9 31 1656 8 207.0 17. 1 17. 1 9.0 \ 32 1733 8 216.6 9.6 9.6 4.6 33 17S7 8 223.4 6.8 6.8 3.1 > 5-5 34 1908 8 238.5 I5-I I5-I 6.8 35 1985 8 248.1 Q.6 9.6 4.2 J 36 2057 8 257.1 9.0 9.0 3-6 ^ 37 2114 8 264.2 7-1 7-1 2.8 38 2254 8 281.7 17.5 17-5 6.6 K 3-8 39 2303 8 287.9 6.2 6.2 2.2 40 2394 8 299.2 ir-3 II-3 3.9 J 42 2572 8 321.5 22.3 III 3.7 \ 44 2742 8 342.7 21.2 10.6 3-3 46 2841 8 355-1 12.4 6.2 1.8 V 2.5 48 2634 7 376.3 21.2 10.6 3-0 50 3064 8 383-0 6.7 3-3 •9 J APPENDIX II 261 GROWTH OF CHICKENS. B. YENiA'LY.'n-yContimird) Total Daily Per Cent. Increase Av. Daily Per Cent. Increase Age Days Weight Obs. Average Over Last Measurement A V eragc Daily Increase Grams 52 3209 8 401. 1 18. 1 9.0 2.3 1 54 56 3430 8 428.7 27,6 13-8 3-4 34 58 426 I 426.0 —2.7 —.7 — . I 8.2 ^ 60 3973 8 496.6 70.6 35-3 62 4255 8 531-9 35-3 17.6 3.5 s 64 4274 8 534-2 2.3 I.I .2 2.4 66 4639 8 579-9 45-7 22.8 4-3 =■ 68 4861 8 607.6 27.7 13.8 2-4 70 72 74 5021 8 627.6 20.0 10. 1.6 j 5538 8 692.2 64.6 16. 1 2.4 \ 76 i 2-5 78 707 I 707.0 14.8 3-9 •5 \ 80 5398 7 771. 1 64.1 32.0 4.5 ) 82 6592 8 824.0 52.9 26.9 3-4 1 86 6924 8 865.5 41-5 10.4 1.2 1.7 90 7093 8 886.6 21. 1 5-3 .5 \ 94 98 8173 8 1021.6 13s. l6.g 19 J 102 8981 8 1122.6 lOI.O 25.2 2.5 ) 1.6 I 106 9552 8 JI94-0 71-4 17.8 1-5 110 9742 8 1217.7 23-7 5.9 .5 s 115 120 10593 8 1324-1 106.4 10.6 ■9 1 125 9831 7 1404.4 80 3 16. 1 .8 130 1 1492 8 1436-5 32.1 6.4 135 12087 8 1510.9 74 4 14.9 I.O .6 j 140 12456 8 1557-0 46.1 9 2 192 15786 8 1973.2 416.2 8.0 •5 ) •5 197 16546 8 2068.2 950 19.0 1.0 202 16551 8 2068.9 .7 .1 .00 ) 335 17276 8 2159 5 90.6 .7 •03 ) 341 16985 8 2123. I —36-4 —6.1 -•3 \ . 2 351 17535 8 2191.9 68.8 69 .3 ) APPENDIX III. DEATH OF PROTOZOA IN 1877 I pointed out that a Protozoon cannot be directly com- ' pared with a Metazoan ^^Proceedings Boston Society of Natural History^ April i8th, p. 170), and in 1879 formulated this opinion more clearly. Since each Metazoon consists of many successive generations of cells, it really is a cell cycle, and can only be homologised with a cycle of protozoan generations, not with any single Protozoon, which is but a single cell. Hence it follows that the death of an individual Protozoon is not homologous with the death of an individual multicellular animal. Weismann committed the fundamental error of assuming the complete homology of the two forms of death, and thus reached the false conclusion that Protozoa are all certainly potentially immortal. The error is all the more important because without assuming its truth the whole speculative structure of germ plasm hypotheses cannot stand. As Oskar Hertwig has already expounded in the first part of his Zeit und Streitfragen the de- pendence of Weismann's " Keimplasm " doctrines upon the incorrect hypothesis of Protozoon immortality, it is unnecessary to discuss the matter further. Concerning Weismann's notions about death a few words may be added. His view was first published in 1882, in his essay Ueber die Dauer des Lebens, and it has been again advocated in his article Ueber Leben und T^'a:' (1884), and has been defended by him subsequently.' Weismann missed the real problem, which is whether Protozoa like Metazoa develop in senescent cell cycles. My position is unchanged, and is clearly presented by the following quotation from an article in the American Naturalist : " He [Weismann] misses the real problem. The following ' E. g , Biologlsclies CfutralblaU., iv., p. 690. 262 APPENDIX HI 263 reasoning leads to this decision. Protozoa and Metazoa consist of successive generations of cells ; in the former the cells sep- arate ; in the latter they remain united ; the death of a Protozoon is the annihilation of a cell, but the death of a Metazoon is the dissolution of the union of cells. Such a dissolution is the result of time, that is to say, of the period necessary to the natural duration of life, and we call it, therefore, ' natural death.' Moreover, we know that natural death is brought about by gradual changes in the cells until, at last, certain cells, which are essential to the preservation of the whole, cease their func- tions. Death, therefore, is a consequence of changes which progress slowly through successive generations of cells. These changes cause senescence, the end of which is death. If we wish to know whether death, in the sense of natural death, properly so called, occurs in Protozoa or not, we must first possess some mark or sign, by which we can determine the occurrence or absence of senescence in unicellular organisms. "Around this point the whole discussion revolves. Certainly a simpler and more certain conclusion could hardly be drawn than that the death of a Metazoon is not identical, i.e., homol- ogous, with the death of a single cell. Weismann tacitly assumed precisely this homology, and bases his whole argument on it. In all his writings upon this subject, he regards the death of a Protozoon as immediately comparable with the death of a Meta- zoon. If we seek from Weismann for the foundation of this view we shall have only our labour for our pains. Starting from this view Weismann comes to the strictly logical conclusion that the Protozoa are immortal. This is a paradox ! In fact, if one compares death in the two cases, from Weismann's standpoint, then we must assume a difference in the causes of death, and conclude that the cause in the case of the Protozoa is external only, while in the Metazoa it is internal only, for, of course, we may leave out of account the accidental deaths of Metazoa. If we approach the problem from this side, we encounter the following principal question : Does death from inner causes occur in Protozoa ? Weismann gives a negative answer to this 2 64 AGE, GROWTH, AND DEATH question, with his assertion that unicellular organisms are im- mortal. The assertion remains, but the proof of the assertion is lacking. In order to justify the assertion, it must be demon- strated that there does not occur in Protozoa a true senescence, showing itself gradually through successive generations of cells. Has Weismann furnished this demonstration? Certainly not. He has, strictly speaking, not discussed the subject. It is clear that we must first determine whether natural death from senes- cence occurs in Protozoa or not, before we can pass to a scientific discussion of the asserted immortality of unicellular beings. The problem cannot be otherwise apprehended. Weismann has not thus conceived it, therefore the judgment stands against him : he misses the real problem" E. Maupas' has maintained that among unicellular animals loss of vitality (senescence) and actual rejuvenation could be demonstrated. He was the first to follow a colony of Protozoa through a long series of generations with a view to determining the changes in the life cycle. His conclusion is that there is an actual exhaustion of the cells going on with the progress of the generations, and that conjugation must occur to effect " rejeu- nissement " (rejuvenescence) otherwise the cells of the cycle die off. Similar experiments have been made in this country by G. N. Calkins,' who likewise concludes that the development of Protozoa is cyclical, the end of the cycle coming through senile degeneration of the cells, and new cycles beginning by a re- juvenation effected by conjugation. If these conclusions are correct we must expect to find proof of cyclical development in other Protozoa. Maupas and Calkins leave a fundamental question undecided. ' E. Maupas, Archives de Zool. Expcr., i., 299 ; i., i\il (1883) ; vi., 165 (1888) ; vii., 149(1880). ^ G. N. Calkins, " Studies in the Life History of Protozoa," Arch. fur. Eii- tivickelungs mechanik, xv., 139-186, also Biol. Bulletin, iii., 192-205, and Journ. Exp. Zool., i., 423-461 (1904). A compreliensive and later presentation of Calkins's views on the protozoan life cycle is given by him in chapter xvii. of the first volume of Osier's Modern Medicine (1907); see especially pp. 361-367. APPENDIX in 265 If it be admitted that the mark of senescence in the Metazoa is increase in the proportion of protoplasm, and the mark of reju- venation increase of the nuclei, then we must expect similar variations in the protozoa, if there be true senescence and re- juvenation among them. It is probable that the observations to decide this question can be made without serious difficulty, and indeed I think they will soon be successfully accomplished. Professor Richard Hertwig has also developed views concern- ing the death of Protozoa, which are certainly interesting, sug- gestive, and important and have been summarised by the author in a special article.' He accepts the views of Calkins as to ''''depression" among Protozoa, but thinks that a further explanation is necessary to explain senescence among Metazoa. I quote from p. 23 of reprint : " Die Teilungsfahigkeit der Zellen eines ausgewachsenen Menschen oder Tieres ist also nicht erloschen, sie ist nur nicht im Stande sich zu betatigen ; sie ist zuriick- gehalten. . . . Mit anderen worten die Zellen eines hoch- entwickelten Tieres teilen sich nicht, weil sie den Wachsthums- gesetzen des Ganzen unterworfen sind, wie ein jeder von uns den Gesetzen des Staates." I agree with Professor Hertwig that the inhibition of growth plays an extremely important role in the higher animals, but as this whole volume argues, I think that cytomorphosis produces true senescence of individual cells, and that this senescence is more fundamental and essential than the inhibitory control. The paper by M. Hartmann^ on Death, I have not seen. From a review of it in the Zoologisches Ceiitralblatt., 1907, 543, I infer that he has revived the idea that reproduction is the cause of death. He is said to maintain that natural death does occur among the protozoa. The review cited says: "Das Resultat seiner Erorterungun fasst unser Autor dahin zusammen dass alien Pro- tozoeii (Protisten ueberhaupt)'ein natiirlicher Tod zukommt und dieser ausnahmslos mit der Fortpflanzung zusammenfallt." ' R. Hertwig, "Uber die Ursache des Todes," Beilage zur Allgemeinen Zci~ tung, Dez. 12 u. 13, igo6. ^ M. Hartmann, Tod und Fortpflatiztitig, Miinchen, igo6. APPENDIX IV. LONGEVITY OF ANIMALS A UGUST WEISMANN in his essay on Lebensdauer has col- **• lected many data in regard to the longevity of animals. It is by far the best compilation of the sort known to me. Mr. F. A. Lucas, Curator of the Brooklyn Museum, has given me some additional facts, and by his courtesy I am allowed to publish the following quotation from a letter which he addressed to me on November 27, 1907: "So far as we know the Aldabra tortoises have reached the greatest age — from ninety to one hundred and fifty years. Of this we may be positive. Carp 'are said' 'to have lived over a hundred years,' and I should not be surprised if this were true. I doubt much if any mammals attain such an age. Until I went to Newfoundland in 1903 I had credited the whale with living to a very great age, but my examination of the many specimens I saw there leads me to doubt this. I discussed the matter a little in Nature and in Science, but the gist of the matter is this — if whales lived indefinitely there should be an indefinite number of sizes, whereas the animals fall into comparatively few groups as regards size, and I now doubt if the whale lives much more than twenty-five years, though this is a mere guess. Observations made on the Pribilof Islands during the past ten years show that the fur seals probably do not reach the age of twenty years with which they have been credited and the fur seal is a fairly large mammal. Even in regard to reptiles, which have been supposed to grow very slowly and almost indefinitely, recent observations have shown that the Galapagos tortoise and our own alligator may grow quite rapidly." 266 APPENDIX V. THEORY OF LIFE T'^HE abstract of the paper on the theory of life, referred to on * p. viii., is here reprinted because it still indicates the starting point of the studies, the results of which are given in the current volume. So little have we gained since 1S79 i^^ ^^^ comprehen- sion of the basic phenomena of living things that were I to rewrite the abstract in accordance with present knowledge I should not change it essentially. The vitalistic hypothesis still seems to me scientifically the best. On the Conditions to be Filled by a Theory of Life. By Charles Sedgwick Minot, of Boston, Mass. [abstract.] It has been so often asserted that the essential nature of life cannot be discovered by man, that the remark has become commonplace. It would seem that this assertion is merely the assumption of haste, and is based only upon our present igno- rance of vital properties. It should rather be said that the main object of all botanical and zoological studies is ultimately to dis- cover the vital principle. The conviction that such is the end of biological research has led me for several years past to endeavour to sort out those vital phenomena which are most universal, in order to determine what are the principal and essential functions of living bodies. Such a labour cannot add much that is new to science, but it forced me to the conclusion that the favourite speculations of the present time concerning the origin and nature of life as explained by science were superficial and even crude, principally because they were not based upon a careful examina- tion of the phenomena to be explained. In order to avoid erro- 267 268 AGE, GROWTH, AND DEATH neous opinions I have deferred publication for a long time, during which, however, no very essential improvement of the outline I had drawn has occurred to me. To deal with such difficult and dangerous questions with complete success requires more know- ledge and judgment than I possess ; I hope, therefore, to be al- lowed to publish what follows rather as opinions I deem plausible, than as conclusions I believe certain. Of one thing, however, I feel sure — that it is useless to discuss the opposing claims of con- scious automatism, the mechanical theory of life and a vital prin- ciple, until we decide what are really the vital phenomena to be explained. All the higher animals and plants are known to consist of col- onies of cells. There are beside many unicellular animals and plants. Of late years there have been described a large number of organisms stated to consist solely of protoplasm. It is on these discoveries that the various protoplasm theories of life have been founded. Many popular articles have been written beginning with the assertion that protoplasm is a simple, jelly-like mass, and ending with the conclusion that life depends solely on the mechanical properties of protoplasm. I think it cannot be too seriously regretted that respectable periodicals have published so many of such articles, because all but the ignorant know that protoplasm is not jelly-like, and not simple ; on the contrary, it consists of many and various chemical compounds, and from recent investigations it has become probable that it never exists as a homogeneous mass, but always contains numerous vacuoles, each enclosing some distinct substance or substances, liquid or solid ; this structure explains the appearance of the so-called protoplasmatic network. Moreover, protoplasm probably can- not permanently maintain its life when separated from a nucleus.' The number of protoplasmatic animals supposed to be without nuclei has rapidly diminished, — especially as the nucleus of the 1 By this I mean only, that all vital functions cannot be performed, because to some of them the nucleus is necessary. Of course protoplasm may remain alive when separated from the nucleus, but the possibility of reproduction is probably lost. APPENDIX V 269 Foraminiferje has been discovered, and the unicellular nature of the Infusoria established. To say that all the supposed proto- plasmatic animals have a nucleus is not yet safe, but it must not be forgotten that in many cases the nucleus is discoverable when properly searched for with the aid of nice histological methods, and that those cases where it has not been found as yet are all cases of uncertainty, partly because careful observations have not been made, partly because the objects themselves are too minute. The probability, therefore, is against the separate existence of protoplasm, and is in favour of the universal presence of the nucleus. This view is strengthened by the discovery of the real nature of Bathybius. A cell must, therefore, be regarded as the unit of life, and the problem we are considering becomes to determine the general properties and functions of cells. I reason chiefly upon the basis of zoology, that branch of biology which alone I have studied scientifically. The principal peculiarities of cells, as thus deter- mined, I consider to be as follows : 1. Irritability. When some motion strikes the cell it may simply act mechanically or give rise to peculiar effects which oc- cur only in living matter. Nothing but some mode of motion ever acts as a stimulus. The effect produced by stimuli is a sen- sation. The stimuli may come from the outside or from the in- side of the cell. The ultimate effects of the irritation may be inhibited,' — that is delayed or prevented by the cell itself. 2. The power of doing work, or developing in response to a stimulus, or from some other cause, a certain amount of motion or energy. The work done may be mechanical, electrical, calo- rific, or even luminiferous. The power of doing work cannot be sustained indefinitely, hence the phenomena of fatigue or exhaustion, and recovery. 3. To set free energy by chemical changes; each cell must be supposed to maintain a vortex by which matter is continually drawn in from the outside, the elements re-combined, and finally in part ejected, while the shape of the vortex or cell is preserved. 2 70 AGE, GROWTH, AND DEATH 4. Grozuih. The cell retains permanently a portion of the matter drawn in by the vortex. 5. Multiplication. The cell cannot grow beyond a certain limit, but instead of further enlargement it divides. (The bud- ding of Infusoria is only a peculiar form of cell division.) 6. Senescence. With each successive generation of cells the power of growth diminishes. Were this otherwise, the growth of each individual at any given time would be in geometrical progression. This loss of power I term senescence. 7. Rejuvenation. The effects of senescence are overcome by some of the cells separating in character from the rest, and giving rise to peculiar bodies, the eggs and spermatozoa. A new cycle of cell generations is thus formed. In each cycle there is a slow senescence terminating in the formation of a new cycle by the rejuvenating influence of the sexual products. 8. Material continuity of life. The actual continuity of living matter is unbroken in consequence of the nature of cell division and of the origin of the sexual products. We cannot, therefore, yet conceive the origin of life, especially as all attempts to demonstrate spontaneous generation have been unconvincing. 9. Heredity. Every cell inherits the qualities of its parents, though imperfectly. The resemblance of an animal to its parent is due to the fact that a given cell of the parent cycle transmits an influence to the child cycle, tending to cause a similar cell to be developed in the same place and at the same time in the off- spring. Heredity is imperfect, both inherently and from the effects of external circumstances. 10. Direct influence of external circumstances. This has now become established in several cases. 11. Predetermined union of cells. When the cells of one cycle unite to form an animal, they arrange themselves definitely in three sets (germ layers), at least in the higher metazoa. 12. Vital union of cells. Some of the cells of each set are united by means of the nerves into a common neural union or association, each member of which loses some of its originality and independence as an individual cell, and becomes able to affect the APPENDIX V ■ 271 other members of the union both in their growth, nourishment, and sensations. 13. Teleological mechanism. This principle has been recently clearly formulated by Pfliiger — a need causes its own satisfaction, e.g.^ the need of digestion produced by the presence of food causes the secretion of the digestive fluids. 14. Memory. Man knows by introspection that he has mem- ory; we attribute it to the higher animals by common consent, and there is no reason for denying its existence in the lower forms. Real memory implies consciousness, otherwise it cannot be known that the sensation refers to the past. 15. Habit. This may be best defined as unconscious memory. It seems to me a grave error to identify habit and real memory. Habit implies that acts become easier if repeated. 16. Consciousness. Our knowledge of this, as of memory, is introspective, and is attributable to animals for the same reasons. 17. Free will. If there be such a thing it must of course be entered here. ^These are the essential categories of the phenomena of animal life, and as they are all performed by colonies of cells, they must be the work of the units of such colonies, or in other words each one of these properties is that of a cell. There are reasons for thinking that unicellular animals have the same properties. To summarise, every cell performs all functions : 1. Responds to stimuli. 2. Maintains the vortex. 3. Grows and divides. 4. Inherits, varies, and bequeaths. Further, each cell probably has 5. A sexual power, usually dormant. 6. Consciousness. 7. Memory. 8. Habit. 5 72 AGE, GROWTH, AND DEATH To explain life we must discover why it displays itself only in a physical basis composed of various albumenoid molecules, imbibed with water and certain salts, and commingled with other complex organic compounds, all disposed in a definite order; why this basis divides into distinct masses, cells, grouped each around a distinct body, the nucleus ; why chemical and physical events take place in a particular order in each cell, the regulating power being within the cell itself; why senescence and rejuvena- tion take place ; and finally the sources of consciousness, memory, and habit. No mechanical explanation, or theory of conscious automatism suffices, but a vital force is the only reasonable hypothesis; the nature of that force is, for the present, an entire mystery, and before we can expect to discover it we must settle what are the phenomena to be explained by it. [From the Proceedings of the American Association for the Advancement of Science, vol. xxviii., Saratoga Meeting, August, 1879.] APPENDIX VI. THE AGE-RECKONER IN making records of growth it is advantageous to weigh the animals at definite ages, using the same ages in all cases. As it is somewhat laborious to calculate the proper dates for an animal born on a given day, the age-reckoner, herewith figured, was devised. It does away with all calculation, for after setting the machine for a given birth-date, all the dates on which weighings are to be made can be read off at once. The apparatus as shown in the figure consists of two metal wheels close together on a single axle. The rims of the wheels are broad and each one bears 365 lines, one for each day in the year. The right-hand wheel is inscribed with the months and days of the month, for example, " yV>?>i>