New Pork State Gallege of Agriculture At Gornell University Dthara, N. Y. Library | ! | 1 iT 2 503 sam Cornell University The original of this book is in the Cornell University Library. There are no known copyright restrictions in the United States on the use of the text. http://www.archive.org/details/cu31924003092503 MONOGRAPHS ON EXPERIMENTAL BIOLOGY EDITED BY JACQUES LOEB, Rockefeller Institute T. H. MORGAN, Columbia University W. J. V. OSTERHOUT, Harvard University THE BIOLOGY OF DEATH BY * “RAYMOND PEARL THE JOHNS HOPKINS UNIVERSITY MONOGRAPHS ON EXPERIMENTAL BIOLOGY THE BIOLOGY OF DEATH Being a Series of Lectures Delivered at the Lowell Institute in Boston in December 1920 BY RAYMOND PEARL THE JOHNS HOPKINS UNIVERSITY PHILADELPHIA AND LONDON J. B. LIPPINCOTT COMPANY COPYRIGHT, 1922, BY J. ». LIPPINCOTT COMPANY PRINTED BY J. B. LIPPINCOTT COMPANY AT THE WASHINGTON SQUARE PRESS PHILADELPHIA, U. S, A, TO MY WISEST. COUNSELLOR M. D. P. EDITOR’S ANNOUNCEMENT THe rapidly increasing specialization makes it im- possible for one author to cover satisfactorily the whole field of modern Biology. This situation, which exists in all the sciences, has induced English authors to issue series of monographs ‘in Biochemistry, Physiology, and Physics. A number of American biologists have decided to provide the same opportunity for the study of Experimental Biology. Biology, which not long ago was purely descriptive and speculative, has begun to adopt the methods of the exact sciences, recognizing that for permanent progress not only experiments are required but that the experi- ments should be of a quantitative character. It will be the purpose of this series of monographs to emphasize and further as much as possible this development of Biology. Experimental Biology and General Physiology are one and the same science, by method as well as by contents, since both aim at explaining life from the physico-chemical constitution of living matter. The series of monographs on Experimental Biology will therefore include the field of traditional General Physiology. Jacques Lors, T. H. Moreayn, W. J. V. OsrerHovr. 7 AUTHOR’S PREFACE In preparing the material of a series of lectures, given at the Lowell Institute in Boston in December 1920, for book publication, I have deemed it on the whole best to adhere rather closely to the original lecture mode of pre- sentation with all its informality. Except for the fact that the matter is here set forth in somewhat greater detail than was possible under the rigid time limitations of the Lowell Institute, and that the breaking into chap- ters is slightly different, the whole is substantially as it was presented in Boston. What I tried to do in these lectures was to bring together under a unified viewpoint some of the more im- portant contributions which have been made to our know- ledge of natural death, from three widely scattered sources: namely general biology, experimental biology, and statistical and actuarial science. It will be obvious to anyone who knows the literature from these fields regarding natural death and the duration of life that in such an amount of space as is here used, no one could hope to cover a field so wide with anything approaching completeness. To do so would require a series of volumes in place of one small one. But this has in no wise been my object; I have instead hoped that the very incomplete- ness itself of this work, necessitated by my limitations of space and knowledge, might stimulate the reader to penetrate for himself further into the literature of this fascinating and important field of biology. To help him to start upon this excursion a brief bibliography is appended. It by no means completely covers the field, but may perhaps serve as an introduction. 9 10 AUTHOR’S PREFACE I am indebted to a number of authors and publishers for permission to use illustrations and wish here to ex- press my great appreciation of this courtesy. The indi- vidual sources for these borrowed figures are in every case indicated in the legends. To Dr. J. McKeen Cattell I am especially grateful for allowing me the use of the blocks from the magazine publication of this material in the Scientific Monthly; to Dr. Alexis Carrel for permis- sion to use unpublished photographs of his tissue cultures ; and, finally, to Professor T. H. Morgan for critically reading the manuscript and making many helpful suggestions. R. P. BALTIMORE, April 19, 1922, CONTENTS CHAPTAR PAGB T, DSS PROBLEM asses reanieecamad aacas seems pea ee eeu ate 17 II. Conprrions oF CELLULAR IMMORTALITY ..........-0-0e ee eee 51 TIT. Toe Cuances or DEATH............ cece eee e cere ere eens 79 WW, Tue Causes oF DEATH. ........0cccccececeeee eens eeeseues 102 DY. EMBRYOLOGY AND Human MORTALITY.........-...00ceeeeeee 138 VI. Tue IngeERITANCE oF Duration or Lirp IN Man ............ 150 VII. EXPERIMENTAL STUDIES ON THE DURATION oF LIFE ......... 186 VIII. Naroray Drata, Posiic HEALTH, AND THE POPULATION PROBLEM 223 BIBLIOGRAPHY. schist oslarss ss Suauesassieg tanaye is lanes ae daresg aban oe taedaarten sl aayale aides 259 ILLUSTRATIONS FIG. PAGE 1. Photograph of John Shell, claimed to be 131 years old, but actually about 100, with his wife and putative son (From Nascher)...... 26 2. Showing the changes in nerve cells due to age (From Donaldson BEGET HOG BE ) ea cess cin via sical aspsvace wra,oes dean rdvaravdhate dotpereiecgbianale ce axe 29 3. Paramecium, viewed from the oral surface (From Jennings)........ 31 4. Diagram showing the process of reproduction by fission in the uni- cellular organism Paramecium,.............e0cceecceesceeees 82 5. Conjugation in Paramecium ..............-cccccencuceceucecves 82 6. Planaria dorotocephala (From Child)................0.c0eeeeees 34 7. Beginning of process of agamic reproduction by fission in Planaria (CBromn Civ) sic.ccs sescia te aceananniaa hacia eeawabeetee 2k aa maeand 35 8. Progress of agamic reproduction in Stenostomum (From Child).... 36 9. Section across the posterior part of an embryo dog-fish (Acanthias) of 3.5mm. (From Minot after Woods).................e0005 38 10. First and second division in egg of Cyclops (From Child).......... 39 11. Diagram to show mode of descent (Modified from Jennings)....... 41 12. Artificially parthenogenetic frogs (Loeb).................0 eee ee 52 13. Piece of tissue from frog embryo cultivated in lymph (From Harrison) 58 14. Group of nerve fibers which have grown from an isolated piece of neural tube of a chick embryo (From Harrison after Burrows).... 59 15. Human connective tissue cells fixed and stained with Giemsa stain (After Losee and Ebeling).............. 0. cc cece eee e et eeeees 60 16. Pennaria (From Wilson). ......... 0.0: cess cece eee e ee c eee ecncees 62 17. Culture of old strain of connective tissue (Ebeling)................ 63 18; Life: table:dia pram + <= Fra. 4—Diagram showing the process of reproduction by Fie, 5—Conjugation fission in the unicellular orginism Paramecium. in Paramecium, pidly growing to full adult magnitude. The essential gross features of this process are illustrated in Figure 4. One cannot say, after the act of fission is accomplished, which is parent and which is offspring. One individual simply becomes two and, in the process of becoming two, loses totally its own identity as an individual. Upon occa- sion another process known as conjugation may intervene. In this process two individuals mate together. By a process of assortative mating, like sizes pair together, THE PROBLEM 33 as was first shown by the writer and later confirmed by Jennings. After pairing has occurred an interchange of nuclear substance occurs by a mechanism described and figured in many elementary textbooks of zoology. This process of conjugation need not further concern us here, for the reason that Woodruff, in the work already referred to, has shown that this phenomenon is not essential to the continued life of the race. Its place may be, and normally very frequently is, taken by the process called endomixis. In this process there occurs a nuclear break- down and reorganization which appears to be the equiva- lent, functionally at least, of that which takes place during conjugation. There has been much discussion, particularly among European workers, as for example Doflein, Jollos, Wede- kind, Slotopowski, and others, about certain philosophi- cal, not to say metaphysical, aspects of immortality in the Protozoa. But all such discussion has in no wise dis- turbed or altered the plain physical fact that there is no place for death in a scheme of reproduction by simple fission, such as is illustrated in Figure 4. Nothing is left at any stage to fulfill the proverbial scheme of ‘‘dust to dust and ashes to ashes.’’ When an individual is through its single individual existence it simply becomes two indi- viduals, which go on playing the fascinating game of living here and now. In a few of the simplest and most lowly organized groups of many-celled animals or Metazoa this power of multiplication by simple fission, or budding off a portion of the body which reproduces the whole, is retained as afacultative asset. This process of reproduction in which the somatic or body cells of one generation produce the somatic cells of the next generation has been called agamic reproduction. It occurs as the more usual but not 3 34 BIOLOGY OF DEATH. Fia, 6.—Planaria dorotocephala: oh meus r Pao te al al, alimentary tract; ns, nervous THE PROBLEM 35 exclusive mode of reproduction, in some or all forms of the three lowest groups of multicellular organisms; the sponges, flatworms, and coelenterates. More rarely it 6 00) Fic.—7. Begin- ning of process of agamic repro- duction by fis- sion in planaria. (From Child) may occur in other of the lower invertebrate groups. It may occur in the form of budding or of fission comparable to that of the Proto- zoa. The agamic reproduction of one of the flatworms, Planaria dorotocephala, studied by the writer many years ago, as shown in Figure 6, may serve as an illustration. This simply organized worm, which lives under stones in sluggish streams and ponds, after attaining a certain size, will under the appropriate environmental conditions exhibit a constriction towards the posterior end of the body, as shown in Figure 7. For a time the animal moves about as a rather ungainly double individual. It finally separates intotwo. The larger anterior part forms a new tail, and the smaller posterior fission product forms a new head and rapidly grows to full size. The process is, in princi- ple, exactly the same as the multiplication of Paramecium by fission. In another member of the same general group of animals as Planaria, named Stenostomum, several fis- sion planes may form and the process start anew before the products delimited by the first plane have separated. As a result, we get frequently in this form chains of individ- uals attached in a long string to each other, as shown in Figure 8. It is obvious that so long as reproduction goes on in 36 BIOLOGY OF DEATH a > ARG hd a I. I. I.1. II. : 1.1.1. 7 5 : ne 1.1.2. 2 a r 1.1.2. 2. ag 1.2.1. 2. > e 1.2.2. 2.1. 2.02. 38 2.2. = p 2.5.2. (oa 39 2.2 49 Fig. 8—Progress of agamic reproduction in Stenostomum: the sequence in the formation of ne 6 zooids is fadieated by the numerals. (From Child.), ” THE PROBLEM 37 this manner in these multicellular forms there is no place for death. In the passage from one generation to the next no residue is left behind. Agamic reproduction and its associated absence of death occurs very commonly in plants. Budding and propagation by cuttings are the common forms in which it is seen. The somatic cells have the capacity of continuing multiplication and life for an indefinite duration of time, so long as they are not acci- dentally caught in the breakdown and death of the whole individual in which they are at the moment located. Thus virtually every apple tree in every orchard in this coun- try is simply a developed branch or bud of some original apple tree from which it was cut, in many cases centuries ago. Apple trees cannot of their own unaided efforts propagate either buds or cuttings. So, until the interven- tion of man, some apple trees died natural deaths, somati- cally speaking, just as do the higher animals of which we shall speak presently. But their cells were inherently capable of better things, as was demonstrated when man first cut off a shoot from an old apple tree and provided it with a root by grafting.* Then it went on and made a new tree. From it in turn cuttings were taken, and so the process has continued to the present day. A part of the soma of one generation produces the soma of the next generation and goes on living indefinitely. A different mode of reproduction is characteristic of higher multicellular animals, and in all but the lowest groups is the exclusive method. A new individual is started by the union of two peculiar cells of extraordinary potentialities, called germ cells. These germ cells are of two sorts, ova and spermatozoa. In bisexual organisms * This provision of roots was not essential, only practically convenient. The cutting would, if enough pains were taken, grow its own roots. 38 BIOLOGY OF DEATH the former are borne in the female, and the latter in the male body. Both sorts undergo a complicated prepara- tion for union, the result of which is that when union does occur each party to it contributes either an exactly equal or an approximately equal amount of hereditary mate- Fia, 9.—Section across the posterior part of an embryo dog-fish (acanthias) of 3.5 mm., to show the compact cluster of germ cells on one side. The germ cells in later stages migrate from this primative position, moving singly orin small groups. Ect, ectoderm: Md, medullary canal or primitive spinal cord; Nch, notochord; Mes, mesoderm: Ent, entoderm: X, cellular strand connecting the germ cell cluster with the yolk. (From Minot after Woods, with the permission of the publishers, G. P. Putnam's Sons). rial. After union has taken place the fertilized ovum or zygote presently begins to divide, first into two cells, these again to four and so on, until by a continuation of this process of division with concomitant differentiation the whole body is formed. As the animal develops by« repeated cell division and differentiation, it is frequently found that at the very early stage the cells which are to be the germ cells of the next generation are clearly re- THE PROBLEM 39 cognizable by their structure, and often are set aside in a definite location in the developing embryo. Thus, to take but a single example of a phenomenon of wide generality, at a very early stage in the development of the dog-fish, when the only bodily organs of which even the rudiments are recognizable are the beginnings of what will presently become the spinal cord and the back-bone, _ Fic. 10.—First division in egg of Cyclops, showing at one pole of spindle the granules which mark the germ path. (From Child, after Amma, by permission of University of Chicago Press). it was shown by Woods, many years ago, that the germ cells are definitely localized and recognizable, as shown in Figure 9. In some forms, notably the round-worm Ascaris, va- rious crustacea and insects, the cells which are to become germ cells are visibly set apart from the very first or one of the first three or four cleavages of the fertilized ovum. For example, in the case of the crustacean Cyclops, Amma has shown that the granules visible at one pole in the very first division mark the prospective germ path, as shown in Figure 10. In the gnat Chironomus the same thing is visible at a very early cleavage, according to the observations of Harper. For a comprehensive and critical review of the 40 BIOLOGY OF DEATH extensive literature on the Keimbahn one should consult the recent contributions of Hegner on the subject. To condense a long and complicated matter we may state the situation regarding reproduction and death in the Metazoa in this way. A higher, multicellular indivi- dual may be conceived, from the viewpoint of the present discussion, as composed of two essentially independent portions: the germ cells on the one hand, which are im- mortal in the same sense that the Protozoa are immortal, and the rest of the body, which it is convenient to call technically the soma, on the other hand. The soma under- goes natural death after an interval of time which, as we have seen, varies from species to species. The germ cells which the individual bears in its body at the time of its death of course die also. But this is purely accidental death so far as concerns the germ cells. Such of them as were, prior to the death of the soma, enabled to unite with other germ cells went on living just as does the dividing Paramecium. Reduced to a formula we may say that the fertilized ovum (united germ cells) produces a soma, and more germ cells. The soma eventually dies. Some of the germ cells, prior to that event, produce somata and germ cells, and so on in a continuous cycle which has never yet ended since the appearance of multi- cellular organisms on the earth. The contrast between the protozoan and the metazoan method of descent is shown in Figure 11, which is a modi- fication of a similar diagram originally due to my col- league, Dr. H. 8. Jennings. The diagram represents the descent of generations. The upper portion of the diagram shows the mode of descent in forms reproducing from organisms reproduc- ing from a single parent. The lower, or B portion of the THE PROBLEM 41 diagram shows the mode of descent in form reproducing from two parents. The lines represent the lives of indi- viduals (as in A diagram), or of germ cells (in the B Fig. 11. Diagram to show mode of descent in (A) unicellular animals reproducing agamic- ally, and in (B) multicellular animals reproducing by germ cells. For further explanation see text. (Modified from Jennings). diagram) beginning at the left and passing to the right. In the A diagram, which represents uniparental reproduc- tion by fission, the line of ancestry traced back from any individual at the right is always single, and there is no corpse to be found anywhere, each present body trans- forming directly into the two bodies of the next generation. 42 BIOLOGY OF DEATH In the B diagram, where we have bi-parental reproduc- tion by the union of germ cells, as in man, the solid black triangles represent the bodies, or somata, and the lines the germ cells. A line of ancestry traced back from any individual towards the right end of the diagram forks at each generation, and in comparatively few generations one has a multitude of ancestors. The bodies of one generation have no continuity with the bodies of the pre- vious or the following generation. In each generation the soma dies, while new somata are reproduced by the union of germ cells from diverse lines. EK. Life itself 1s a continuum. A break or discontin- uity in its progression has never occurred since its first appearance. Discontinuity of existence appertains not to life, but only to one part of the makeup of a portion of one large class of living things. This is certain, from the facts already presented. Natural death is a new thing which has appeared in the course of evolution, and its appearance is concomitant with, and evidently in a broad sense, caused by that relatively early evolutionary spe- cialization which set apart and differentiated certain cells of the organism for the exclusive business of car- rying on all functions of the body other than reproduc- tion. We are able to free ourselves, once and for all, of consequence of life. It is nothing of the sort. Life can and does all the time go on without death. The somatic death of higher multicellular organisms is simply the price they pay for the privilege of enjoying those higher specializations of structure and function which have been added on as a side line to the main business of living things, which is to pass on in unbroken continuity the never-dimmed fire of life itself. THE PROBLEM 43 THEORIES OF DEATH On the basis of these five general classes of facts which have been briefly reviewed a whole series of specu- lations as to the meaning of death have been reared. The first attempt at a biological evaluation* of the meaning of death which attracted the serious attention of scientific men was that of Weismann. In his famous address of 1881 on the duration of life, Weismann propounded the thesis that death was an adaptation, advantageous to the race, and had arisen and was preserved by natural selection. Probably no more perverse extension of the theory of natural selection than this was ever made. It appeared, however, just at the time when the post-Darwinian at- tempt to settle the problems of evolution by sheer dia- lectic was at the zenith of its popularity. Nowadays such a doctrine as Weismann’s would not receive so respectful a hearing. Metchnikoff, whose views excited so much popular interest some years ago, held that death was the result of intoxication, arising from the absorption of putrefac- tive products of the activity of intestinal bacteria. The chief difficulty with this view is that it is demonstrably not true; either particularly in the case of man, where it can easily be shown that many statistically important causes of death cannot possibly be accounted for under it, or generally in the animal kingdom; because a num- ber of cases are now known where a metazoan form can be successfully made to lead a completely aseptic life, and still death occurs at about the usual time. (Cf. Chap- ter VIII). More speculative developments of the same * An excellent discussion of various theories of death, which the writer, though differing from some of the conclusions, has found useful in the preparation of this section, has lately been given by Child in his “Senescence and Rejuvenescence.” 44 BIOLOGY OF DEATH basic idea have been presented by Jickeli and Montgom- ery. Both held that because of the mechanical incomplete- ness of the processes of metabolism, injurious and toxic substances tend to accumulate in the cells of the body, and that senescence and death are the results of such accumulations. A much broader, and in the light of all facts sounder view, is that the determination of degrees of longevity and of the fact of death itself, is inherent in the innate, hereditarily determined biological constitution of the in- dividual and the species. This view was expressed by Johannes Miiller a quarter of a century ago in his Physi- ologie, by Cohnheim forty years later, and has had many later adherents. I shall return to a discussion of it later. There have been a number of theories of senescence and death, differing widely in details, but having the one point in common of attributing these phenomena to orderly changes with advancing age in the relative pro- portion of nucleus to protoplasm in the cells of the body. Here may be mentioned, without pausing to go into de- tailed consideration of their different views, Verworn, Mihlmann, Richard Hertwig, and Minot. Another group of hypotheses, all advanced in com- paratively recent times and associated with the names of Kassowitz, Conklin, and Child, are developed about the metabolic aspects of age changes. There is observed a decrease in assimilatory capacities of cells with differen- tiation and age. These metabolic changes are regarded as fundamentally casual of the phenomena of senescence and death. In this general group of hypotheses would belong the views of my colleague, Dr. W. T. Howard. Benedict in a detailed investigation of senility in plants reaches the conclusion: THE PROBLEM 45 “that the duration of life is directly linked with the degree of permeability in that part of the living cell which places it in contact with the universe about it, and that as the activities of life proceed the cell is being gradually entombed by an inevitable decrease in the permeability of its protoplasm, While decreasing permeability furnishes a possible explanation of the more obvious symptoms of senility, it cannot be the only degeneration of first rank. All protoplasmic functions must be involved. Underlying these primary causes of senile degeneration there must be some general funda- mental cause from which they spring. This fundamental cause may well be the colloidal nature of protoplasm.” Delage and Jennings have considered that death is the result of differentiation. Jennings has put the matter in this way...... “the continuity of life in the infusoria is in principle much like that in ourselves, though with differences in details. As individuals, the infusoria do not die, save by accident. Those that we now see under our microscopes have been living ever since the beginnings of life; they come from division of previously existing individuals. But in just the same sense, it is true for ourselves that everyone that is alive now has been alive since the beginning of life. This truth applies at least to our bodies that are alive now; every cell of our bodies is a piece of one or more cells that existed earlier, and thus our entire body can be traced in an unbroken chain as far back into time as life goes, The difference is that in man and other higher organisms there have been left all along the way great masses of cells that did not continue to live. These masses that wore out and died are what we call the bodies of the persons of earlier generations; but our own bodies are not descended by cell division from these; they are the continuation of cells that have kept on living and multiplying from the earliest times, just as have the existing infusoria,” Jennings’ views regarding senescence in the protozoa will be discussed in the next chapter. Unicellular organisms, as we have seen, do not nor- mally experience natural death. In the higher organisms there has been a progressive setting apart of cells and tissues to perform particular vital functions with a con- sequent loss of the ability to perform all vital functions independently . As soon as any one of these cells or tissues begins, for any accidental cause whatever, to fail to per- 46 BIOLOGY OF DEATH form its special function properly, it upsets the delicate balance of the whole associated community of cells and tis- sues. Because of the differentiation and specialization of function, the parts are mutually dependent upon each other to keep themselves and the whole going. Conse- quently any disturbance in the balance which is not promptly righted by some regulatory process must even- tually end in death. Since the publication of this material in serial form an objection to the foregoing statement has been sug- gested on the ground that differentiation per se does not appear to the critic to have much to do with the question of natural death in the Metazoa. To quote; ‘‘rather it is the failure after differentiation to keep up indefinitely the state reached. If, from any internal or external accident, the differentiated part suffers injury, the injury cannot be made good any more, since in certain organs this power has been lost. Hence, in time, loss after loss occurs and the machine wears out. The protozoan is as highly differ- entiated as any cell of a metazoan (or much more so) ; but since it ‘‘multiplies by dividing,’’ it has retained the power to make good any loss. Therefore, it is not the differentiation per se, but the loss of power to repair that produces senescence.”’ This seems to me to be in the main only a somewhat different form of statement of precisely the idea that I have endeavored to express. When I have used the term ‘‘differentiation’’ in this connection, I have always had in mind, as one of its most important physiological con- comitants, just the thing spoken of above. Furthermore, whether the protozoan cell is as highly differentiated as a metazoan cell, is not to the point at all. For, to have any pertinence so far as the present issue is concerned, the comparison must be between the differentiated proto- THE PROBLEM 47 zoan cell, and the whole metazoan soma, not one of its constituent cells. In the protozoan, all the differentia- tions are in and a part of one single cell operating as one metabolic unit, of small absolute size, and consequently easier and more labile internal physico-chemical regula- tion. In the metazoan soma we have organ differentia- tion, with the constituent cells in each organ highly specialized functionally, and dependent upon the nor- mal functional activity of wholly other organs in order that they may keep going at all. Remove these tissue cells from the soma, and provide them with an abundance of suitable nourishment and oxygen, as in tissue cultures, and, so far as the evidence now available indicates, they will live forever (cf. Chapter II). Consider for a moment the most highly differentiated protozoan known, on the one hand, and man, on the other hand, purely as physico-chemical machines, which only keep going if the internal balances and adjustments are, in each case, held within a narrow zone of normality. Quite aside from any question of their different modes of reproduction, the two machines are not equivalent, as machines, because of :(a) unicellular versus multicel- lular structure, (b) great absolute difference in size of the whole machines, with consequent requirement of an enormously more complex internal regulatory mechanism in the one case than in the other, whatever the inherent nature of this mechanism may be. Essentially the same view of the matter as that held by the present writer has been well set forth by Loeb in his most recent paper on the subject. He says: “All this points to the idea that death is not inherent in the individual cell, but is only the fate of more complicated organisms in which different types of cells or tissues are dependent upon each other. In this case it seems to happen that one or certain types of cells produce a substance or substances which gradually become harmful to a vital organ like the res- 48 BIOLOGY OF DEATH piratory center of the medulla, or that certain tissues consume or destroy substances which are needed for the life of some vital organ. The mischief of death of complex organisms may then be traced to the activity of a black sheep in the society of tissues and organs which constitute a com- plicated multicellular organism.” At this point I shall not stay to discuss critically each of the hypotheses so summarily reviewed. Instead, I shall make bold to state somewhat categorically my own views on the origin and meaning of death and the deter- mination of longevity ; and in what follows, shall endeavor to set forth in orderly array the evidence which seems to me to support these views. In this process, the relations of what I shall suggest to the conclusions of earlier inves- tigators will, I think, sufficiently appear. Let us consider, then, the following picture of life and death: 1. Life itself is inherently continuous. 2. Living things, whether single-celled or many- celled organisms, are essentially only physico-chemical machines of extraordinary complexity; but regardless of their degree of complexity only amenable to, and activated in accordance with, physical and chemical laws and principles. 3. The discontinuity of death is not a necessary or inherent adjunct or consequence of life, but is a rela- tively new phenomenon, which appeared only when and because differentiation of structure and function appeared in the course of evolution. 4. Death necessarily occurs only in such somata of multicellular organisms as have lost, through differentia- tion and specialization of function, the power of repro- ducing each part if it, for any accidental reason breaks down or is injured; or still possessing such power in their cells, have lost the necessary mechanism for separating a THE PROBLEM 49 part of the soma from the rest for purposes of agamic reproduction. 5. Somatic death results from an organic disharmony of the whole organism, initiated by the failure of some organ or part to continue in its normal harmonious func- tioning in the entire differentiated and mutually depend- ent system. This functional breakdown of a part may be caused in a multitude of ways from external or internal sources. It may manifest itself in a great variety of ways both structurally and functionally. Many of these manifestations which have been regarded as causes of senescence, may more truly be considered concomitant attributes of senescence. 6. As a consequence of our second thesis which postu- lated life to be a mechanism, death, whether of a single somatic cell or of a whole soma, is a result of physico- chemical changes in the cell or organism; and these changes are in accordance with ordinary physico- chemical laws and principles. 7. The time at which natural death of the soma occurs is determined by the combined action of heredity and environment. For each organism there is a specific long- evity determined by its inherited physico-chemical con- stitution. This specific longevity is capable of modifica- tion, within relatively narrow limits, as a result of the impact of environmental forces; the chief mode of action of the environment being in the direction of determining the rate at which the inherited endowment is used up. For no one of the separate elements of this picture can I claim any particular originality. Most of them would probably be agreed to at once, at least by some biologists. The need is for a synthesizing into a consistent whole of a wide range of data, which have accumulated in various 4 50 BIOLOGY OF DEATH fields of biology, about death and the duration of life. Such a synthesis will be attempted in what follows. Generally, those who have speculated about the biology of death have drawn their evidence from, or at least had their thinking largely colored by the facts in a relatively small part of the whole field. In particular, few biologists have any detailed knowledge of the most impressive mass of material, both in respect of quality and quantity, which exists regarding the duration of life of any organ- ism. I refer, of course, to the enormous volume of rather exact data regarding human mortality. Much of this material, to be sure, wants proper analysis, not only mathematical but biological. But, that it is a rich material admits of no doubt. CHAPTER II CONDITIONS OF CELLULAR IMMORTALITY In the preceding chapter it was pointed out that the germ cells of higher organisms are potentially, and under certain conditions in fact, immortal. What are the con- ditions of immortality in this case? Are they such as to support the thesis that the processes of mortality are essentially physico-chemical in nature, and follow physico-chemical laws? ARTIFICIAL PARTHENOGENESIS The most essential condition of this immortality of germ cells was mentioned, but not particularly empha- sized. It is that two germ cells, an ovum and a spermato- zoon unite, the process of union being called fertilization. Having united, if they then find themselves in appro- priate environmental conditions, development goes on; new germ cells and a soma are formed, and the same process keeps up generation after generation. Now, while union of the germ cells is generally and in most organisms an essential condition of this process, it is also true that in a few forms of animal life, mostly found among the invertebrates, development of the ovum can take place without any preceding fertilization by a spermatozoon. The process of reproduction, in this case is called par- thenogenesis. In a number of forms in which partheno- genesis never occurs normally, so far as is known, it can be induced by appropriate extraneous procedures. The discovery of this extraordinarily interesting and impor- tant fact for a number of organisms, and the careful 51 52 BIOLOGY OF DEATH working out of its physico-chemical basis, we owe to Dr. Jacques Loeb, of the Rockefeller Institute for Medical Research. Artificial parthenogenesis may be induced, as Guyer, Bataillon and Loeb have shown, even in so highly organized a creature as the frog, and the animal may grow to full size. The frogs shown in Figure 12, while they present an appearance much the same as that of any other frog of the same species, differ in the rather fundamentally important respect that they had no father. The role of a father was played in these cases by an ordinary dissecting needle. Unfertilized eggs from a virgin female were gently pricked with a sharply pointed needle. This initiation of the process of development took place March 16, 1916, in one case, and February 27, 1917, in the other. The date of death was, in the first case, May 22, 1917, and in the other March 24, 1918. In the course of Loeb’s studies of parthenogenesis in lower marine invertebrates, he became interested in the question of the death of the germ cells which had failed to unite, or, having united, failed of appropriate envi- ronmental conditions. His researches throw light on some of the conditions of cellular death, and on that account they may be reviewed briefly here. He found that the unfertilized mature eggs of the sea-urchin die compara- tively soon when deposited in sea-water. The same eggs, however, live much longer, and will, if appropriate sur- rounding conditions are provided, go on and develop an adult organism, if they are caused to develop artificially by chemical means or naturally by fertilization. Loeb concluded from this that there are two processes going on in the egg. He maintained, on the one hand, that there are specific processes leading to death and disintegration; and, on the other hand, processes which lead to cell divi- CONDITIONS OF CELLULAR IMMORTALITY 83 sion and further development. The latter processes may be regarded as inhibiting or modifying the mortal pro- cess. Loeb and Lewis’ undertook experiments, based upon this view, to see whether it would be possible by chemical treatment of the egg to prolong its life. Since in general specific life phenomena are perhaps, on the chemical side, chiefly catalytic phenomena, it was held to be reasonable that if some substance could be brought to act on the egg, which would inhibit such phenomena without permanently altering the constitution of the living material, the life of the cell should be considerably prolonged. The first agent chosen for trial was potassium cyanide, KCN. It was known that this substance weakened or inhibited entirely a number of enzymatic processes in living material, without materially or permanently alter- ing its structure. It was found that, normally, the unfertilized egg of the sea-urchin would live in sea-water at room temperature, and maintain itself in condition for successful fertiliza- tion and development, up to a period of about twenty-three hours. After that time the eggs began to weaken. Hither they could not be successfully fertilized, or if they were fertilized, development only went on for a short time. After 32 hours, the eggs could not, as a rule, be fertilized at all. The experiment was then tried of adding to the sea-water, in which the unfertilized eggs were kept, small amounts of KCN in a graded series, and then exam- ining the results of fertilizations undertaken after a stay of the unfertilized eggs of 75 hours in the solution. It will be noted that this period of 75 hours is more than three times the normal duration of life of the cell in normal sea-water. The results of this experiment are shown in summary form in Table 4. 54 BIOLOGY OF DEATH TABLE 4 Experiments of Loeb and Lewis on the Prolongation of Life of the Sea-urchin Egg by KCN Concentration of Result of fertilization after a 75 hours’ stay KCN in the solution Pure sea-water No egg segments n/64000 KCN No egg segments n/16000 KCN No egg segments n/8000 KCN Very few eggs show a beginning of seg- mentation n/4000 KCN Very few eggs show a beginning of seg- mentation n/2000 KCN Few eggs go through the early stages of segmentation n/1000 KCN Many eggs segment and develop into swim- ming larve n/750 KCN Many eggs segment and develop into swim- y ming larvee n/400 KCN A few eggs develop into swimming larve n/300 KCN No egg segments n/250 KCN No egg segments ; n/200 KCN No egg segments n/100 KCN No egg segments From this table it is seen that in concentrations of KCN from n/750 to n/1000 the eggs developed perfectly into swimming larve. In other words, by the addition of this very small amount of KON, the life period has been prolonged to three times what it would normally be under the same environmental conditions. Concen- trations of KCN weaker than n/1000 were incapable of producing this result, or at best, if development started, the process came very quickly to an end. In stronger concentrations than n/400 the eggs were evidently poi- soned, and no development occurred. Other experiments of Loeb’s show that the lethal effects of various toxic agents upon the egg cell may be inhibited or postponed for a relatively long time, by CONDITIONS OF CELLULAR IMMORTALITY 55 suitable chemical treatment, such as lack of oxygen, KCN, or chloral hydrate. A typical experiment of this kind made upon the sea-urchin, Strongylocentrotus purpuratus may be quoted: Eggs were fertilized with speym and put eleven minutes later into three flasks, each of which contained 100 c. c. of sea-water + 16 c. c. 2-12 m CaCl. One flask was in contact with air, while the other two flasks were connected with a hydrogen generator. The air was driven out from these two flasks before the beginning of the experiment. The eggs were transferred from one of these flasks after four hours and fourteen minutes, from the second flask after five hours and twenty-nine minutes, into normal (aerated) sea-water. The eggs that had been in the hypertonic sea-water exposed to air were transferred simultaneously with the others into separate dishes with aerated normal sea-water. The result was most striking. Those eggs that had been in the hypertonic sea-water with air were all completely disintegrated by “black cytolysis.’ Ten per cent. of the eggs had been transformed into “shadows” (white cytolysis). It goes without saying that all the eggs that had been in the aerated hyper- tonic sea-water five and a half hours were also dead. The eggs that had been in the same solution in the absence of oxygen appeared all normal when they were taken out of the solution, and three hours later—the temperature was only 15°C.—they were all, without exception in a per- fectly normal two- or four-cell stage. The further development was also in most cases normal. They swam as larve at the surface of the vessel and went on the third day (at the right time) into a perfectly normal pluteus stage, after which their observation was discontinued. Of the eggs that had been five and a half hours in the hypertonic sea-water deprived of oxygen, about 90 per cent. segmented. Let us consider one more illustration from Loeb’s work in this field. Normally, in the forms with which he chiefly worked, sea-urchin, starfish, and certain mol- luses, an absolutely essential condition for the continua- tion of life of the germ-cells after they are discharged from the body is that two cells, the ovum and the sper- matozoon, shall unite in normal fertilization. Put in another way, parthenogenesis does not normally occur in these forms. Fertilization is an essential condition for the continuation of life and development. But Loeb’s 1 56 BIOLOGY OF DEATH painstaking and brilliant’ researches, extending over a number of years, show that when we say that fertilization is an essential condition for the continued life of the germ-cells outside the body, our language tends to ob- scure the most important fact, which is simply that for the continuation of life in these cells only certain internal physico-chemical conditions and adjustments must be realized. It makes no essential difference to the result whether these conditions are realized through the intervention of the sperm, as in normal fertiliza- tion, or by purely artificial chemical methods initiated, controlled and directed at every step by human agency. We can, in other words, regard all cases of suc- cessful artificial parthenogenesis as fundamentally a con- tribution to the physiology of natural death, and a demon- stration of its essentially mechanistic basis. The condi- tions of continued existence are physical and chemical, and controllable as such. The methods finally worked out as optimum afford a complete demonstration of the thesis we have just stated. Thus, for example, the unfertilized egg of the sea-urchin, Strongylocentrotus purpuratus, will continue in life and develop perfectly normally if it is subjected to the following treatment: The eggs are first placed in sea-water to which a definite amount of weak solution of butyric acid has been added (50 ce. of sea-water + 2.8 c.c. n/10 butyric acid). In this solution at 15° C. the eggs are allowed to remain from 114 to 3 or 4minutes. They are then transferred to normal sea-water, in which they remain from 15 to 20 minutes. They are then transferred for 30 to 60 minutes at 15°C. to sea-water which has had its osmotic pressure raised by the addition of some salts (50 c.c. of sea-water+8 c.c. of 214 m NaCl, or 21%4 m NaCl+KCL+CaCl, in the proportion in which these CONDITIONS OF CELLULAR IMMORTALITY 57 salts exist in sea-water). After the stay of from 30 to 60 minutes in this solution, the eggs are transferred back to normal sea-water, the transferring being in batches at intervals of 3 to 5 minutes between each batch transferred. It is then found that those eggs which have been just the right length of time in the hypertonic sea-water develop into perfectly normal sea-urchin larve. In other words, we have here a definite and known physico-chemical pro- cess completely replacing what was, before this work, universally regarded as a peculiarly vital process of extraordinary complexity, probably beyond power of human control. These three examples from Loeb’s work on the sub- ject of prolongation of life in the egg cell will suffice for our present purposes. The lesson which they teach is plain, and is one which has, as will be readily perceived, a most important bearing upon the general concept of life and death outlined in the preceding chapter. The experiments demonstrate that the conditions essential to continued life of the germ-cells outside the body are phy- sico-chemical conditions, and that when these cells die it is because the normal physico-chemical machinery for the continuation of life has either broken down, or has not been given the proper activating chemical conditions. Lack of space alone prevents going in detail into an- other extremely interesting and important development of this subject, due to Dr. Frank R. Lillie of the Univer- sity of Chicago. He has, in recent years made a thorough analysis of the biological factors operating when the egg of the sea-urchin is normally fertilized by a spermato- zoon. The conception of the process of fertilization to which Lillie comes is ‘‘that a substance borne by the egg (fertilizin) exerts two kinds of actions: (1) an agglutin- 58 BIOLOGY OF DEATH ating action on the spermatozoon and (2) an activating action on the egg. In other words, the spermatozoon is conceived, by means of a substance which it bears and which enters into union with the fertilizin of the egg, to release the activity of this substance within the egg.”’ From the standpoint of the present discussion it is ob- vious that Lillie’s results so far present nothing which in any way disturbs the conclusion we have reached as ta the essentially physico-chemical nature of the processes which condition the continuation of life and development of the egg. TISSUE CULTURE IN VITRO Let us turn now to another question. Are the germ- cells the only cells of the metazoan body which possess the characteristic of potential immortality? There is now an abundance of evidence that such is not the case, but that, on the contrary, there are a number of cells and tissues of the body, which, under appropriate conditions, may continue living indefinitely, except for the purely accidental intervention of lethal circumstances. Every child knows that all the tissues do not die at the same time. It is proverbial that the tail of the snake, whose head and body have been battered and crushed until even the small boy is willing to admit that the job of killing is complete, ‘‘will not die until the sun goes down.’’ Galvani’sfamous experiment with the frog’s legs only succeeded because some parts survive after the death of the organism as a whole. As Harrison points out ‘‘ Almost the whole of our knowledge of muscle-nerve physiology, and much of that of the action of the heart, is based upon experiments with surviving organs; and in surgery, where we have to do with changes involved in the repair of injured parts, Fie. 13.—Piece of tissue from frog embryo cultivated in lymph, two days old. The dark portion shows original bit of tissue. Lighter portions are new growth (From Harrison.) Fic. 14.—Group of nerve fibers which have grown from an isolated piece of neural tube of a chick embryo. (From Harrison after Burrows.) CONDITIONS OF CELLULAR IMMORTALITY 59 including processes of growth and differentiation, the power of survival of tissues and organs and their trans- plantability to strange regions, even to other individuals, has long formed the basis of practical procedures.”’ The first successful cultures of somatic cells and tis- sues outside the body were those of Leo Loeb, described in 1897. His first method consisted in cultivating the tissues in appropriate media in test tubes. Later he used also another method, which involved the transplantation of the solid medium and the tissue into the body of an- other animal. What has been regarded as a defect of both these methods is that they do not permit the contin- ued observation of the cells of the growing cultured tissue. To Harrison is due the development of a method which does permit such study. In 1907 he announced the dis- covery that if pieces of the developing nervous system of a frog embryo were removed from the body with, fine needles, under strictly aseptic precautions, placed on a sterile cover slip in a drop of frog lymph, and the cover slip then inverted over a hollow glass slide, that the tis- sues would remain alive for many days, grow and exhibit remarkable transformations. By this technique it was possible to study the changes with a high power micro- scope and photograph them. Figure 13 is a general view of one of these tissue cul- tures two days old. It shows a piece of nervous tissue from the frog embryo, with cells growing out from it into the lymph. The lighter portions are the new cells. In his remarkable monograph Harrison shows nerve cells developing fibers at first thickened, but presently becoming of normal character and size. At the ends are pseudopodial processes, by which the growing fiber at- taches itself to the cover slip or other solid bodies. Fig- 60 BIOLOGY OF DEATH ure 14 shows a particularly beautiful nerve fiber prepar- ation made by Burrows. The fibers grew from a preparation of the embryonic nervous system of the chick. There can be no doubt, as these figures so clearly show, of the life of these cells outside the body, or of the normality of their develop- mental and growth processes. Under the guidance of Harrison, ‘another worker, Burrows, improved the technique of the cultivation of tissues outside the body, first by using plasma from the blood instead of lymph and later in various other ways. He devised an apparatus for affording the tissue culture a continuous supply of fresh nutrient medium. There is in this apparatus a large culture chamber which takes the place of the plain hanging drop in an hermetically sealed cell. On the top of this culture chamber there is a wick, which carries the culture fluid from a supplying chamber and discharges it into a receiving chamber. The tissue is planted among the fibers of the wick, which are pulled apart where it crosses the top of the chamber. The whole system is kept sterile and so arranged that the growing tissue can be kept under observation with high powers of the microscope. The nutrient medium may be modified at will, and the effects of known sub-- stances upon the cellular activities of every sort may be studied. Burrows began his investigations in this field on the tissues of the embryo chick. With the success of these cultures was established the fact that the tissues of a warm blooded animal were as capable of life, develop- ment, and growth outside the body as were those of cold- blooded animals, such as the frog. Burrows succeeded in cultivating outside the body, cells of the central nervous Fia. 15.—Human connective tissue cells fixed and stained with Giemsa stain. The culture was made by extirpating the central portion of culture 285 in its 16th passage, washing the remaining portion of the culture with Ringer solution without removing it from the cover-glass, and drop- ping on tresh plasm and extract. The preparation shows the extent. of growth obtained in 48 hours from peripheral cells remaining after extirpation of the fragment. (After Losee and Ebeling.) CONDITIONS OF CELLULAR IMMORTALITY 61 system, the heart, and mesenchymatous tissue of the chick embryo. At the same time Carrel was carrying on studies in this same direction at the Rockefeller In- stitute. In his laboratory were made the first successful cultures i vitro of the adult tissues of mammals. He developed a method of culture ona plate which permitted the growing of large quantities of material. He found that almost all the adult and embryonic tissues of dog, cat, chicken, rat, guinea pig, and man could be cultivated m vitro, Figure 15 shows a culture of human tissue, made at the Rockefeller Institute. I am indebted to Doctor Carrel and Doctor Ebeling for permission to pre- sent this photograph here. According to the nature of the tissues cultivated, con- nective or epithelial cells were generated, which grew out into the plasma medium in continuous layers or radiating chains. Not only could normal tissues be cultivated but also the cells of pathological growths (cancer cells). It has been repeatedly demonstrated that normal cell division takes place in these tissues cultivated outside the body. The complex process of cell division, which is technically called mitosis, has been rightly regarded as one of the most characteristic, because complicated and unique, phenomena of normal life processes. Yet this process occurs with perfect normality in cells cultivated outside the body. Tissues from various organs of the body have been successfully cultivated, including the kidney, the spleen, the thyroid gland, ete. Burrows was even able to demonstrate that the isolated heart muscle cells of the chick embryo can divide as well as differen- tiate, and beat rhythmically in the culture medium. Perhaps even more remarkable than the occurrence of such physiological activity as that of the heart muscle 62 BIOLOGY OF DEATH cells in vitro is the fact that in certain lower forms of life a small bit of tissue or even a single cell, may develop in culture into a whole organism, demonstrating that the capacity of morphogenesis is retained in these isolated somatic cells. H. V. Wilson has shown that in coelenter- ates and sponges complete new individuals may develop in vitro from isolated cells taken from adult animals. By squeezing small bits of these animals through bolting cloth he was able to separate small groups of cells or even single cells. In culture these would grow into small masses of cells which would then differentiate slowly into the normal form of the complete organism. Figure 16 shows an example of this taken from Wilson’s work. It was early demonstrated by Carrel and Burrows that the life of the tissues in vitro, which varied in differ- ent experiments from 5 to 20 days, could be prolonged by a process of successive transfers of the culture to an indefinite period. Cells which were nearing the end of their life and growth in one culture need only be trans- ferred to a new culture medium to keep on growing and multiplying. Dr. and Mrs. Warren H. Lewis made the important discovery that tissues of the chick embryo could be cultivated outside the body in purely inorganic solutions, such as sodium chloride, Ringer’s solution, Locke’s solution, ete. No growth in these inorganic cul- tures took place without sodium chloride. Growth was prolonged and increased by adding calcium and potas- sium. If maltose or dextrose, or protein cleavage pro- ducts were added proliferation of the cells increased. By the method of transfer to fresh nutrient media, Carrel has been able to keep cultures of tissue from the heart of the chick embryo alive for a long period of years. In a letter, recently received, he says: ‘‘The Fie. 16.—Pennaria. Restitution mass six days old, completely metamorphosed, with developed hydranths. Op. perisarc of original mass; x, perisare of outgrowth adherent to glass. (From Wilson.) S years and 8 months old, (Ebeling). 1614 passage. x20 48 hours’ growth. lacking 2 days. Fie. 17,—Culture of old strain of connective tissue. CONDITIONS OF CELLULAR IMMORTALITY 63 strain of connective tissue obtained from a piece of chick heart is still alive, and will be nine years old the seven- teenth of January, 1921.’’ Figure 17 is a photograph showing the present condition of this culture. It should be understood that this long continued culture has gone on at body temperature in an incubator, and not by keep- ing the culture at a low temperature and merely slowing down. the vital processes. This is indeed a remarkable result. It completes the demonstration of the potential immortality of somatic cells, when removed from the body to conditions which permit of their continued existence. Somatic cells have lived and are still living outside the body for a far longer time than the normal duration of life of the species from which they came. I think the present extent of Carrel’s cultures in time fully disposes of Harrison’s criticism to the effect that we are ‘‘not justified in referring to the cells as potentially immortal or even in speaking of the prolongation of life by artificial means, at least not until we are able to keep the cellular elements alive in cultures for a period exceeding the duration of life of the organism from which they are taken. There is at present no reason to suppose this cannot be done, but it simply has not been done as yet.’’ I have had many years’ experience with the domestic fowl, and have par- ticularly studied its normal duration of life, and discus- sed the matter with competent observers of poultry. I am quite sure that for most breeds of domestic poultry the normal average expectation of life at birth is not substantially more than two years. For the longest lived races we know this normal average expectation of life cannot be over four years. I have never been able to keep a Barred Plymouth Rock alive more than seven 64 BIOLOGY OF DEATH years. There are on record instances of fowls living to as many as 20 years of age. But these are wholly excep- tional instances, unquestionably far rarer than the occur- rence of centenarians among human beings. There can be no question that the nine years of life of Carrel’s culture has removed whatever validity may have origin- ally inhered in Harrison’s point. And further the cul- ture is just as vigorous in its growth today as it ever was, and gives every indication of being able to go on indefinitely, for 20 or 40, or any desired number of years. The potential immortality of somatic cells has been logically just as fully demonstrated in another way as it has by these tissue cultures. Some nineteen years ago, Leo Loeb first announced the important discovery that potential immortality of somatic cells could be demon- strated through tumor transplaftations. His latest sum- mary of this work may well be quoted. here: “We must remember that common, transplantable tumors are the direct descendants of ordinary tissue cells, such as we normally find in the individuals of the particular species which we use. The tumors may be derived from a variety of normal tissues and, in general, the transfor- mation from normal cells into tumor cells takes place under the influence of a long continued action of various factors enhancing growth. Tumor cells are, therefore, merely somatic cells which have gained an increased growth energy and at the same time somehow gained, in some cases, the power to escape the destructive consequences of homoiotoxins. This ability of cer- tain tumors to grow in other individuals of the same species has enabled us to prove, through apparently endless propagation of these tumor cells in other individuals, that ordinary somatic cells possess potential im- mortality in the same sense in which protozoa and germ cells possess immortality. Thus tumor transplantation made possible the establishment of a fact of great biological interest, which, because of the homoiosensitive- ness of normal tissues, could not be shown in the latter, “We wish, however, especially to emphasize the fact that our experi- ments did not merely prove the immortality of tumor cells, but of the ordinary tissue cells as well, the large majority or all of which can be transformed into tumor cells. At an early stage of our investigations CONDITIONS OF CELLULAR IMMORTALITY 65 we drew, therefore, on the basis of these experiments, the conclusion that ‘ordinary tissue cells are potentially immortal; notwithstanding the fact that, especially under Weismann’s influence, the opposite view had been generally accepted, and as it seems to us, with full justification, inasmuch as no facts were known at that time which suggested the immortality of somatic cells. It was the apparently endless transplantation of tumor cells which proved the contrary view, , “To recapitulate what we stated above: tumors are merely transformed tissue cells. All or the large majority of adult tissues are potential tumor cells. Tumor cells have been shown experimentally to be potentially im- mortal, therefore tissue cells are potentially immortal. “ This wider conclusion I expressed nineteen years ago. Quite recently,’ the immortality of certain connective tissue cells has been demonstrated by Carrel through in vitro culture of these cells. Under those conditions the tissue cells escape the mechanisms of attack to which the homoiotoxins expose the ordinary tissue cells in other individuals of the same species. Under these conditions the reactions of the host tissue against homoiotoxins which would have taken place in vivo, are eliminated. We must, however, keep in mind that this method of proving the immortality of somatic cells applies only to one particular, very favorable kind of cells; and it is very doubtful, if, by cultivation in vitro, the same proof could be equally well supplied in the case of other tissues. On the basis of tumor transplanta- tions, on the contrary, we were able to show that a considerable variety, perhaps the large majority of all tissue cells possess potential immortality.” To Loeb unquestionably belongs the credit for first perceiving that death was not a necessary inherent con- sequence of life in the somatic cell, and demonstrating by actual experiments that somatic cells could, under cer- tain conditions, go on living indefinitely. Before turning to the next phase of our discussion, let us summarize the ground we have covered up to this point. We have seen that by appropriate control of conditions, it is possible to prolong the life of cells and tissues far beyond the limits of longevity to which they would attain if they remained in the multicellular body from which they came. This is true of a wide variety of cells and tissues differentiated in various ways. In- deed, the range of facts which have been ascertained 5 66 BIOLOGY OF DEATH by experimental work in this field, probably warrants the conclusion that this potential longevity inheres in most of the different kinds of cells of the metazoan body, except those which are extremely differentiated for par- ticular functions. To bring this potential immortality to actuality requires, of course, special conditions in each particular case. Many of these special conditions have already been discovered for particular tissues and particular animals. Doubtless, in the future many more will be worked out. We have furthermore seen that in certain cases the physico-chemical nature of the condi- tions necessary to insure the continuance of life has been definitely worked out and is well understood. Again this warrants the expectation that, with more extended and penetrating investigations in a field of research which is really just at its beginning, we shall understand the physics and chemistry of prolongation of life of cells and tissues in a great many cases where now we know nothing about it. One further point and we shall have done with this phase of our discussion. The experimental culture of cells and tissues in vitro has now covered practically all the essential tissue elements of the metazoan body, even including the most highly differentiated of those tissues. Nerve cells, muscle cells, heart muscle cells, spleen cells, connective tissue cells, epithelial cells from various loca- tions in the body, kidney cells, and others have all been successfully cultivated in vitro. We may fairly say, I be- lieve, that the potential immortality of all essential cel- lular elements of the body either has been fully demonstrated, or else has been carried far enough to make the probability very great that properly conducted experiments would demonstrate the continuance of the CONDITIONS OF CELLULAR IMMORTALITY 67 life of these cells in culture to any definite extent. It 1s not to be expected, of course, that such tissues as hair, or nails, would be capable of independent life, but these are essentially unimportant tissues in the animal econ- omy as compared with those of the heart, the nervous system, the kidneys, ete. What I am leading to is the broad generalization, perhaps not completely demon- strated yet, but having regard to Leo Loeb’s work, so near it as to make little risk inhere in predicting the final outcome, that all the essential tissues of the meta- zoan body are potentially immortal. The reason that they are not actually immortal, and that multicellular animals do not live forever, is that in the differentiation and specialization of function of cells and tissues in the body as a whole, any individual part does not find the conditions necessary for its continued existence. In the body any part is dependent for the necessities of its existence, as for example nutritive material, upon other parts, or put in another way, upon the organization of the body as a whole. It is the differentiation and spe- cialization of function of the mutually dependent aggre- gate of cells and tissues which constitute the metazoan body which brings about death, and not any inherent or inevitable mortal process in the individual cells them- selves. An examination of different lines of evidence has led us to two general conclusions, viz: a. That the individual cells and tissues of the body, in and by themselves, are potentially immortal. b. That death of the metazoan body occurs, funda- mentally, because of the way in which the cells and tis- sues are organized into a mutually dependent system. Is there any further and direct evidence to be had 68 BIOLOGY OF DEATH upon the second of these conclusions? So far our evi- dence in its favor has been indirect and inferential, though cogent so far as it goes. In this connection, a paper of Friedenthal’s is of considerable interest. He shows that there is a marked correspondence between the longevity of various species of animals and a constant of organization which he calls the ‘‘cephalisation factor.’’ This cephalisation factor in pure form, in his sense, is given by the equation. Brain weight Total mass of body protoplasm. Now ‘‘total mass of body protoplasm,’’ as distinct from supporting structures, such as bone etc., is obviously difficult to determine directly. But Friedenthal is well convinced that, to a first approximation, the cephalisa- tion factor may be written in this way: Cephalisation factor = Brain weight .. (Body weight) Computed upon the latter basis he sets up tables of the relation between cephalisation factor and longevity for mammals and for birds. It is not necessary to repro- duce here the long tables, but to show the general point, the following table for five selected species of mammals will suffice: . Cephalisation factor = TABLE 5 Relation between the cephalisation factor and longevity (Friedenthal) Species Cephalisation index Duration of life Muuse 0.045 6 years Rabbit -066 8 years Marmoset (Callithriz) -216 12 years Deer .85 15 years Man 2.7 100 years There appears in this short selected table a defect CONDITIONS OF CELLULAR IMMORTALITY 69 which is even more apparent in his long ones, namely, that the figures for duration of life are distinctly round numbers. There is no evidence, for example, that the normal life span of the mouse is 6 years. All who have statistically studied the matter agree upon a much smal- ler figure than this. But, leaving this point aside, it is apparent that there is a parallelism of striking sort be- tween the cephalisation factor and duration of life. In other words, it appears that the manner in which higher vertebrates, at least, are put together in respect of the proportionality of brain and body is markedly associated with the duration of life. It would be a matter of great interest to see whether this correlation between relative brain-weight and the expectation of life holds intra- racially as well as it does inter-racially. The bearing of these results of Friedenthal’s upon our results as to the distribution of mortality upon a germ-layer basis, to be discussed in Chapter V infra, is obvious. . Another possible illustration of the general point now under discussion may be found in some recent work of Robertson and Ray. These authors, in a recent paper, have analyzed the growth curves of relatively long-lived mice as compared with the curves shown by relatively short-lived individuals. In the experiment both groups were subjected to the same kind of experimental treat- ment of various sorts, and the care with which the experi- ments were conducted in respect of control of the environmental factors renders the results highly inter- esting and valuable. The long-lived animals form a group which grows more rapidly in early life, and at the same time is less variable than the short lived group. The short-lived animals often grow much more rapidly in later life than the long-lived, but this accretion of tissue 70 BIOLOGY OF DEATH was found to be relatively unstable.. They further found that the long-lived animals represent a relatively stable group, highly resistant to external disturbing factors, and showing a more or less marked but not invariable tendency to early overgrowth and relative paucity of tissue accretion in late life. The short-lived animals are on the contrary relatively unstable, sensitive to external disturbing factors, and, as a rule, but not invariably, dis- play relatively deficient early growth and a tendency to rapid accretion of tissue in later life. In interpreting these results, Robertson and Ray be- lieve that the differences are based upon the fact that in early or embryonic life the outstanding characteristic of the tissues is a high proportion of cellular elements, whereas in old age there is a marked increase in connective _ tissues. They further point out that connective tissue “elements are ultimately dependent upon cellular tissues for their support, and that the connective tissues are expensive to maintain. They believe that the reason that the substance tethelin (cf. Chap. VII infra) prolongs life is because it accelerates the metabolism of the cellular elements to the detriment of the connective tissue ele- ments. Longevity on this view is determined not by the absolute mass of living substance, but by the relative proportions of parenchymatous to sclerous tissues. SENESCENCE The facts presented in this and the preceding chapter clearly make it necessary to review with some care the current conception of senescence. Senescence, or grow- ing old, is commonly considered to be the necessary prel- ude to ‘‘natural,’’ as distinguished from accidental death. CONDITIONS OF CELLULAR IMMORTALITY 71 But is the evidence really sound and complete that such is the fact? A careful and unprejudiced examination will inevi- tably suggest to the open mind, I think, that much of the existing literature on senescence is really of no funda- mental importance, because it has unwittingly reversed the true sequential order of the causal nexus. If cells of nearly every sort are capable, under appropriate con- ditions, of living indefinitely in undiminished vigor, and cytological normality, there is little ground for postu- lating that the observed senescent changes in these cells while in the body, such as those described by Minot and others, are expressive of specific and inherent mortal processes going on in the cells; or that these cellular pro- cesses are the cause of senescence, as Minot has concluded. That there is such a phenomenon as senescence is, of course, certain. It is observable both in Protozoa and in Metazoa. The real question, however, is a twofold one, viz: (a) is senescence in either Protozoa or Metazoa an inevitable consequence of the strain or the individual having lived; and (b) is senescence a necessary asso- ciate and forerunner of natural death? Let us briefly reconsider the facts. In Protozoa a slowing down of the division rate in culture has been frequently observed; and it has been held, first, that this is a phenomenon essentially homologous to senes- cence in the metazoan; and second, that if nuclear reorganization, by the way either of endomixis or of conjugation, did not occur that the strain would die out. Indeed, Jennings, in discussing the matter in his last book says: “Thus it appears that in these organisms nature has employed the method of keeping on hand a reserve stock of a material essential to 72 BIOLOGY OF DEATH life; by replacing at intervals the worn out material with this reserve, the animals are kept in a state of perpetual vigor; not, as individuals, growing old or dying a natural death. Nevertheless, a wearing out pro- cess, such as might be called getting old, does occur in the structures employed in the active functions of life, and these must be replaced after a, time of service. So far as the conditions in these organisms are typical, deterioration and death do appear to be a consequence of full and active life; life carries within itself the seeds of death. It is not mating with another individual that avoids this end; but replacement of the worn material by a reserve...... The great mass of cells subject to death in the higher animals dwindles in the infusorian to the macronucleus; this alone represents a corpse. But the dissolution of this corpse occurs within the living body. It much resembles such a process as the wasting away and destruction of minute parts of our own bodies, which we know is taking place at all times, and which does not interrupt the life of the individual.” It is doubtful if this position is warranted. Since Jennings wrote the statement quoted, some new and pertinent data have appeared in regard to amicronu- cleate infusoria. Woodruff and his co-workers have shown that such races may occur rather commonly. Thus Woodruff, in 1921, says: “During the past year, the isolation for certain experiments of 14 “wild” lines representing 6 species of hypotrichous ciliates revealed 7 lines (4 species) with micronuclei and 7 lines (2 species) without morphological micronuclei. Ten of the lines were all isolated from a “wild” mass culture of the same species Urostyla grandis, found in a laboratory aquarium. Six of these lines were amicronucleate. All of the lines of all of the species have bred true with respect to the character in question, and one amicronucleate line at present is at the 102d generation. Similarly a culture of Paramecium caudatum, which the present writer supplied a year ago to a course in protozodlogy for the study of the nucleus, failed to reveal a micronucleus, although in other races the micronucleus was readily demonstrated.” Now, since it is the micronucleus which furnishes for the process of endomixis the ‘‘reserve stock of a material essential to life’? which Jennings discusses, it is plain that the existence of amicronucleate races of Protozoa CONDITIONS OF CELLULAR IMMORTALITY 73 at once puts a new face upon the whole matter. Dawson has studied in continued culture one of these amicronu- cleate races of Oxytricha hymenostoma Stokes. His con- clusion is as follows: “The existence of a form which not only apparently may live indefi- nitely without conjugation, autogamy, or endomixis (assuming the possi- bility of the latter phenomenon in an hypotrichous form), but also apparently does not possess the ability to undergo any of these phenomena, brings to light an entirely new possibility in the life history of ciliates. It has been proved quite conclusively, (Woodruff, 714), that in forms which ordinarily conjugate, the continued prevention of this process brings about no loss of viability if a favorable environment be provided. How- ever, in the organism under consideration there is apparently no possi- bility not only of conjugation or endomixis, but also of autogamy; and thus we have from another source crucial evidence that none of these phenomena is an indispensable factor in the life-history of this hypo- trichous form.” In the light of these clean cut and definite results one is more disposed than was formerly the case to accept at their face value the results of Enriques with Glaucoma pyriformis, and those of Hartmann with Eudorwma elegans, in which reproduction went on indef- initely with undiminished vigor and no evidence of any process comparable to endomixis. Altogether, it seems to me that the weight of the evi- dence now is that in the Protozoa, senescence (or death), is not a necessary or inevitable consequence of life. Given the appropriate and necessary conditions of envi- ronment, true immortality—the absence of both senes- cence and natural death, each defined in the most critical manner—is in fact the reality for a number of forms. Turning to the metazoan side of the case, the evidence regarding senescence is equally cogent. In the first place, in the longest continued in vitro tissue cultures known (those of Carrel) there is, as already stated, no appear- 74 BIOLOGY OF DEATH ance of senescence in the cells. But it may be objected that an element of uncertainty is injected into the case, by the fact that, as Carrel and Ebeling have lately dis- cussed in some detail, it has been necessary in carrying along this long-continued culture to add regularly to the culture medium a small amount of ‘‘embryonic juice.’’ One might urge that, but for the ‘‘embryonic juice,’’ cellu- lar senescence and death would have appeared. But suppose this to be granted fully. It does not mean that senescence is a necessary and inevitable consequence of life, but only that to realize a potential immortality the cells must have an appropriate environment, one element of which ispresumably some chemical combination which, so far, one has supplied only through ‘‘embry- onic juice.’’ An entirely different sort of evidence and one of great significance is found in the facts of clonal propaga- tion of plants, well known to horticulturists. An individ- ual apple tree grows old, and eventually dies, as a tree. But at all periods of its life, including all stages of senescence up to the terminal one, death, it produces shoots each spring. If one of these shoots is grafted to another root, it will, in the passage of time, make first a young tree, then a middle aged tree, and finally an old, senescent tree; which, in turn, will make new shoots, which may, in turn, be grafted to new roots, and so on ad infimtum. It is not even absolutely necessary that the shoot be grafted to a new root; though, of course, this is the manner in which the great majority of our orchards are, in fact, propagated, and have been since the beginning of horticultural history. Anyone who is familiar with the woods of New England, not too far from settlements, has seen apple trees in the woods where a CONDITIONS OF CELLULAR IMMORTALITY 75 shoot, whose continuity with the base of its parent tree has never been broken, makes a new tree after the old one has died—indeed in some cases the shoot has helped the mortiferous process by the vigorous crowding of youth. In this whole picture how fares any idea of the necessity or inevitableness of cellular (somatic) senescence? Such an idea plainly has no place in the realities of the con- tinued existence of apple trees. From these facts it is a logically cogent induction to infer that when cells show the characteristic senescent changes which were discussed in the preceding chapter, it is because they are reflecting in their morphology and physiology a consequence of their mutually dependent association in the body as a whole, and not any necessary progressive process inherent in themselves. In other words, may we not tentatively, in the light of our present knowledge, regard senescence as a phenomenon appear- ing in the multicellular body as a whole, as a result of the fact that it is a differentiated and conferentiated (to employ a useful term lately introduced by Ritter) mor- phologic and dynamic organization. This phenomenon is reflected morphologically in the component cells. But it does not primarily originate in any particular cell because of the fact that that cell is old in time, or because that cell in and of itself has been alive; nor does it occur in the cells when they are removed from the mutually dependent relationship of the organized body as a whole and given appropriate physico-chemical condi- tions. In short, senescence appears not to be a primary attribute of the physiological economy of cells as such. If this conception of the phenomenon of senescence is correct in its main features, it suggests the essential futility of attempting to investigate its causes by purely 76 BIOLOGY OF DEATH cytological methods. On the other hand, by clearing away the unessential elements, it indicates where research into the problem of causation of senescence may be profitable. An extremely interesting contribution to the problem of senescence has been made by Carrel and Ebeling in their most recent paper, in which they show that the rate of multiplication of fibroblasts in vitro, and the duration of life of such cultures, is inversely proportional to the age of the animal from which the serum for the culture medium is taken. These results are of such considerable interest that it will be well to quote in full the summary of them given by the authors: “Pure cultures of fibroblasts displayed marked differences in their activity in the plasma of young, middle aged, and old chickens. The rate of cell multiplication varied in inverse ratio to the age of the animal from which the plasma was taken. There was a definite relation between the age of the animal and the amount of new tissue produced in its plasma in a given time. The chart obtained by plotting the rate of cell prolifera- tion in ordinates, and the age of the animal in abscisse, showed that the rate of growth decreased more quickly than the age increased. The de- crease in the rate of growth was 50 per cent. during the first 3 years of life, while in the following 6 years it was only 30 per cent. When the duration of the life of the cultures in the four plasmas was compared, a curve was obtained which showed about the same characteristics. The duration of life of the fibroblasts in vitro varied in inverse ratio to the age of the animal, and decreased more quickly than the age increased. “As the differences in the amount of new tissue produced in the plasma of young, middle aged, and old chickens were large, the growth of a pure culture of fibroblasts could be employed as a reagent for detect- ing certain changes occurring in the plasma under the influence of age. “A comparative study of the growth of fibroblasts in media containing no serum, and serum under low and high concentrations was made, in order to ascertain whether the decreasing rate of cell multiplication was due to the loss of an accelerating factor, or to the increase of an inhibiting one. In high and low concentrations of the serum of young animals, no difference in the rate of multiplication of fibroblasts was observed. This showed that the serum of an actively growing animal did not contain any accel- THE CHANCES OF DEATH 77 erating agent. The same experiments were repeated with the serum of a 3 year old and a 9 year old chicken. The medium made of a high concentration of serum had a markedly depressing effect on the growth, and this effect was greater in the serum of the older animal. “The results of the experiments showed in a very definite manner that certain changes occurring in the serum during the course of life can be detected by modifications in the rate of growth of pure cultures of fibro- blasts and that these changes are characterized by the increase of an inhibiting factor, and not by the loss of an accelerating one. It appeared, therefore, that the substances which greatly accelerate the multiplication of fibroblasts and are found in the tissues do not exist in the blood serum, or are constantly shielded by more active inhibiting factors. The curve which expresses the variations of the inhibiting factor in function _of_the age was compared with that showing the variations of the rate of healing of = wound @GsOFaIE tthe age of the gubject For wounds of equal size, the index of cicatrization, which expresses the rate of healing, varies in inverse ratio to the age. The different values of the index of cicatrization of a wound 40 sq. cm. in area, taken from measurements made by du Noiiy, were plotted in ordinates, and the age of the subject in abscisse. The curve showed a decrease in the activity of cicatrization, which resembled the decrease in the rate of growth of fibroblasts in function of the age of the ‘animal. This suggested the existence of a relation between the factors determining both phenomena.” These results suggest that there is produced in some cases by the body or some of its parts, a_ substance which inhibits the power of cells to multiply or to remain alive. How general such a phenomenon is in occurrence does not yet appear, but, apparently, it must be absent in the case of clonal reproduction in plants already dis- cussed, and in the analogous case of agamic reproduction in lower Metazoa (cf. planarians). It seems possible that the results of Carrel and Ebeling might be open to a slightly different interpretation than that which they give, which hypothecates a specific inhibiting substance in the serum, increasing in either amount or specific potency with age. It seems to me that all of their facts could be interpreted with equal cogency on the supposi- tion that the serum from an old animal is itself senes- 78 BIOLOGY OF DEATH cent as a whole; that is, has undergone a physico-chemi- cal alteration (as compared with that of a young ani- mal), which is comparable to the morphological and physiological changes which are observable in senescent cells. It may further quite reasonably be supposed that ‘‘senescent’’ serum, because of these physico-chemical alterations, does not furnish so favorable a nutrient me- dium for in vitro cultures as does ‘‘young’’ serum. Such a view avoids the necessity of postulating a specific ‘“senescent’’ substance, the existence of which would be exceedingly difficult to prove. But in any case, whatever explanation is suggested for Carrel and Ebeling’s brilliant results, it does not seem to me that the results themselves, which alone are the realities pertinent in the premises, either offer any obstacle to or, indeed, alter the interpretation of senes- cence which I have suggested above. For, what the re- sults really demonstrate is, essentially, that the serum of old animals is a less favorable component of the nutrient medium of cells in vitro than is the serum of young ani- mals. This fact is a contribution to our knowledge of the phenomena and attributes of senescence of first-class importance; but it does not per se, as it appears to me, permit of any new generalization as to the etiology of senescence. CHAPTER III THE CHANCES OF DEATH THE LIFE TABLE Up to this point in our discussion of death and lon- gevity we have, for the most part, dealt with general and qualitative matters, and have not made any particular examination as to the quantitative aspects of the prob- lem of longevity. To this phase attention may now be directed. For one organism, and one organism only, do we know much about the quantitative aspects of longevity. I refer, of course, to man, and the abundant records which exist as to the duration of his life under various condi- tions and circumstances. In 1532 there began in London the first definitely known compilation of weekly ‘‘Bills of Mortality.’? Seven years later, the official registra- tion of baptisms, marriages and deaths was begun in France, and shortly after the opening of the seventeenth century similar registration was begun in Sweden. In 1662 was published the first edition of a remarkable book, a book which marks the beginning of the subject which we now know as ‘‘vital statistics.’’ I refer to ‘‘Natural and Political Observations Mentioned in the Following Index, and made upon the Bills of Mortality’’ by Captain John Graunt, Citizen of London. From that day to this, in an ever widening portion of the inhabited globe we have had more or less continuous published records about the duration of life of man. The amount of such material. which has accumulated is enormous. We are only at the 79 80 BIOLOGY OF DEATH beginning, however, of its proper mathematical and bio- logical analysis. If biologists had been furnished with data of anything like the same quantity and quality for any other organism than man it is probable that a vastly greater amount of attention would have been devoted to them than ever has been given to vital statistics, so-called, and there would have been as a result many fundamental advances in biological knowledge now lacking, because material of this sort so generally seems to the profes- sional biologist to be something about which he is in no way concerned. Let us examine some of the general facts about the normal duration of lifein man. We may put the matter in this way: Suppose we started out at a given instant of time with a hundred thousand infants, equally distributed as to sex, and all born at the same instant of time. How many of these individuals would die in each succeeding year, and what would be the general picture of the changes in this cohort with the passage of time? The facts on this point for the Registration Area of the United States in 1910 are exhibited in Figure 18, which is based on Glover’s United States Life Tables. In this table are seen two curved lines, one marked 1 « and the other d,. The J, line indicates the number of individuals, out of the original 100,000 starting together at birth, who survived at the beginning of each year of the life span, indicated along the bottom of the diagram. The d, line shows the number dying within each year of the life span. In other words, if we subtract the num- ber dying within each year from the number surviving at the beginning of that year we shall get the series of figures plotted as the /, line. We note that in the very first year of life the original hundred thousand lose over THE CHANCES OF DEATH 81 one-tenth of their number, there being only 88,538 sur- viving at the beginning of the second year of life. In the next year 2,446 drop out, and in the year following that 1,062. Then the line of survivors drops off more slowly between the period of youth and early adult life. At 40 years of age, almost exactly 30,000 of the original 100,000 have passed away, and from that point on the J, line descends with ever increasing rapidity, until about UNITED STATES LFE TABLE - iO Sol \ 4 NS oli Sad ee ee eS Sg as ar 30 BS Boas = YEARS OF LIE Fra. 18.—Life table diagram. For explanation see text. age 80, when it once more begins to drop more slowly, and the last few survivors pass out gradually, a few each year until something over the century mark is reached, when the last one of the 100,000 who started across the bridge of life together will have ended his journey. This diagram is a graphic representation of that im- portant type of document known as a life or mortality table. It puts the facts of mortality and longevity in their best form for comparative purposes. The first such table actually to be computed in anything like the modern fashion was made by the astronomer, Dr. H. Halley, and 6 82 BIOLOGY OF DEATH was published in 1693, although thirty years before that time Pascal and Fermat (cf. Levasseur) had laid down certain mathematical rules for the calculation of the probabilities of human life. Since Halley’s time a great number of such tables have been calculated. Dawson fills a stout octavo volume with a collection of the more important of such tables, computed for different coun- tries and different groups of the population. Now they have become such a commonplace that elementary classes in vital statistics are required to compute them (see for example Dublin’s New Haven life table). CHANGES IN EXPECTATION OF LIFE I wish to pass in graphic review some of these life tables in order to call attention in vivid form to an impor- tant fact about the duration of human life. In order to bring out the point with which we are here concerned it will be necessary to make use of another function of the mortality table than either the / or dz lines which are shown in Figure 18. I wish to discuss expectation of life at each age. The expectation of life at any age is defined in actuarial science as the mean or average number of years of survival of persons alive at the stated age. It is got by dividing the total survivor-years of after life by the number surviving at the stated age. Or, if we let ee denote what is called the curtate expectation of life eg = tet t beet Enlai +th+n To a first approximation, sufficiently accurate for our present purposes, the total expectation of life, called @, , may be obtained from the curtate expectation by the simple relation er = ez + 1/2 THE CHANCES OF DEATH 83 TABLE 6 Changes in expectation of life from the seventeenth century to the present time Average length of life remaining Average length of life remaining to each one alive at beginning to each one alive at beginning of age interval of age interval Age Age Breslau, | Carlisle, Breslau, | Carlisle, 17th 18th U.S. 1910 17th 18th | U.S.1910 century century century century o- 1 33.50 38.72 51.49 50- 51 16.81 21.11 20.98 1- 2 38.10 44.67 57.11 51- 52 16 .36 20.39 20.28 2-3 39.78 47.55 57.72 52- 53 15.92 19.68 19.58 3- 4 40.75 49, 57.44 53- 54 15.48 18.97 18.89 4-5 41.25 50.76 56.89 54- 55 14.99 18.27 18.21 5- 6 41.55 51.24 56.21 55- 56 14.51 17.58 17.55 6- 7 41.62 1.16 55.47 56- 57 14.02 16.89 16.90 7-8 41,16 50.79 54.69 57- 58 13.54 16.21 16 .26 8- 9 40.95 50.24 53.87 58- 59 13.06 15.55 15.64 9-10 40.50 49.57 53.02 59- 60 12.57 14.92 15.03 10-11 39.99 48 .82 52.15 60- 61 12.09 14.34 14.42 11-12 39.43 48.04 51.26 61- 62 11.62 13.82 13.83 12-13 38.79 47.27 50.37 62- 63 11.14 13.31 13.26 13-14 38.16 46.50 49.49 63- 64 10.67 12.81 12.69 14-15 37.51 45.74 48 .60 64- 65 10.20 12.30 12.14 15-16 36.86 44.99 47.73 65- 66 9.73 11.79 11.60 16-17 36.22 44.27 46.86 66- 67 9.27 11.27 11.08 17-18 35.57 43.57 46.01 67- 68 8.81 10.75 10.57 18-19 34.92 42.87 45.17 68- 69 8.36 10.23 10.07 19-20 34.26 42.16 44.34 69- 70 7.91 9.70 9.58 20-21 33.61 41.46 43.53 70- 71 7.53 9.17 9.11 21-22 32.95 40.75 42.73 71- 72 7.17 8.65 8.66 22-23 32.34 40.03 41.94 72- 73 6.85 8.16 $92 23-24 31.67 39.31 41.16 73- 74 6.56 7.72 7.79 24-25 31.00 38.58 40.38 74- 75 6.25 7.33 7.38 25-26 30.38 37.86 39.60 75- 76 5.99 7.00 6.99 26-27 29.76 37.13 38.81 76- 77 5.79 6.69 6.61 27-28 29.14 36.40 38.03 77- 78 5.71 6.40 6.25 28-29 28.51 35 .68 37.25 78- 79 5.66 6.11 5.90 29-30 27.93 34.99 36.48 79- 80 5.67 5.80 5.56 30-31 27.35 34.34 35.70 80- 81 5.74 5.51 5.25 31-32 26.76 33.68 34.93 81- 82 5.86 5.20 4.96 32-33 26.18 33 .02 34.17 82- 83 6.02 4.93 4.70 33-34 25.59 32.36 33.41 83- 84 5.85 4.65 4.45 34-35 25.05 31.68 32.66 84— 85 4.39 4.22 35-36 24.51 31.00 31.90 85- 86 4.12 4.00 36-37 23.97 30.32 31.16 86- 87 3.90 3.79 37-38 23.43 29.63 30.42 87- 88 3.71 3.58 38-39 22.88 28.95 29.68 88- 89 3.59 3.39 39-40 22.33 28.27 28.94 89- 90 3.47 3.20 40-41 21.78 27.61 28 .20 90- 91 3.28 3.03 41-42 21.23 26.97 27.46 91- 92 3.26 2.87 42-43 20.73 26.33 26.73 92- 93 3.37 2.73 43-44 20.23 25.71 25.99 93- 94 3.48 2.59 44-45 19.72 25.08 25.26 94- 95 3.53 2.47 45-46 19,22 24.45 24.54 95- 96 3.53 2.35 46-47 18.72 23.81 23.82 96- 97 3.46 2.24 47-48 18.21 23.16 23.10 97- 98 3.28 2.14 48-49 17,71 22.50 22.39 98- 99 07 2.04 49-50 17.25 21.81 21.69 99-100 2.77 1.95 In each of the series of diagrams which follow there is plotted the approximate value of the expectation of 84 BIOLOGY OF DEATH life for some group of people at some period in the more or less remote past, and for comparison the expectation of life, either from Glover’s table, for the population of the United States Registration Area in 1910—the expec- tation of life of our people now, in short—or equivalent figures for a modern English or French population. Because of the considerable interest of the matter, and the fact that the data are not easily available to HALLEY'S BRESLAU 687 - 1691 LIFE TABLE 6 55 aa NX sa N _ ad J N 420 Ta AN fre Nag Re] NK See Ae Aa erat oe en, cl < OS 10 520 25 30 35 40 45 30 35 0051075 80 8590 95 100 YEARS OF AGE Fic. 21.—Comparing the expectation of life of Ancient Egyptians with that of present i day Americans. Plotted from Pearson’s and Glover's data. For comparison, the expectation of life from Glover’s 1910 United States life table is inserted. It will be seen at once that the general sweep of the line is of the same sort that we have already observed in the case of the seventeenth century table. In the early years of life the expectation was far below that of the present time, but somewhere between ages 65 and 70 the Egyptian line crosses the modern American line, and from that period on the individuals living in Egypt at about the time of the birth of Christ could apparently look forward toa longer remaining duration of life, on the aver- THE CHANCES OF DEATH 89 age, than can the American of the present day. Pearson’s comment on this fact is worth quoting. He says: ‘In the course of those centuries man must have grown re- markably fitter to his environment, or else he must have fitted his environment immeasurably better to himself. No civilized community of to-day could show such a.curve as the civilized Romano-Egyptians of 2,000 years ago exhibit. We have here either a strong argument for the survival of the physically fitter man or for the survival of the civilly fitter society. Hither man is constitution- ally fitter to survive to-day, or he is mentally fitter, 7.e., better able to organize his civic surroundings. Both con- clusions point perfectly. definitely to an evolutionary progress. . . . That the expectation of life for a Romano-Egyptian over 68 was greater than for a modern English man or woman is what we might expect, for with the mortality of youth and of middle age enormously emphasized only the very strongest would survive to this age. Out of 100 English alive at 10 years of age 39 survive to be 68; out of 100 Romano-Egyptians not 9 survived. Looking at these two curves we realize at a glance either the great physical progress of man, which enables him far more effectually to withstand a hostile environment, or the great social and sanitary progress he has made which enables him to modify the environ- ment. In either case we can definitely assert that 2,000 years has made him a much ‘fitter’ being. In this com- parison it must be remembered that we are not placing a civilized race against a barbaric tribe, but comparing a modern civilization with one of the highest types of ancient civilization.’’ Macdonell was able to continue this investigation on much more extensive material extracted from the Corpus 90 BIOLOGY OF DEATH Inscriptionum Latinarum of the Berlin Academy, which gives records as to age of death for many thousand Roman citizens dying, for the most part, within the first three or four centuries of the Christian era. His mate- rial may, therefore, be taken to represent the conditions a few centuries later than those of Pearson’s Romano- Egyptian population. Macdonell was able to calculate - as ss Lead ee aw UNITED STATES 50 SASS KS. te 45 mS & 40 3 x “ANY ee ca 's S 30 RAN g : i SS m2 SS 20 |e tec pe fend a ace a ee WS Pe a i— WS i ~~ ms ROME Sy SN - SS a a — ps ‘ 0 5 10 18 20 25 30 35 40 45 50 53 60 70 75 8085 8085100 YEARS OF AGE Fre, 22.—Comparing the expectation of life of Ancient Romans with that of present day Americans. Plotted from Macdonell’s and Glover's data. three tables of expectation of life—the first for Roman citizens living in the city of Rome itself; second for* those living in the provinces of Hispania and Lusitania; and third, for those living in Africa. The results are plotted against the United States 1910 data, as before, in Figures 22, 23, and 24. Figure 22 relates to inhabitants of the city of Rome itself. The deaths from which the expectations are calculated run into the thousands, and fortunately one is able to separate males and females. As in Pearson’s case, which we have just examined, modern American THE CHANCES OF DEATH 91 data are entered for comparison. It will be noted at once that just as in the Romano-Egyptian population the expectation of life of inhabitants of ancient Rome was, in the early years of life, apparently immensely inferior to that of the modern population. From about the age of 60 on, however, the expectation of life appears to have been better then than now. Curiously enough, the expectation : Hel = = IN ——— ss NM UNITED STATES $0 a 45 zc s Ne a0 - eS NW h Ske oe EN IN = 30 PN SN S ‘< = Eas we Qu a bs NS N oN] ~ 2 20 , o~ —e SS FEMA ? No eet et és ae ieee en eel CTS 2o 40 2) 60 100 YEARS OF UFE Fia. 25.—Showing Pearson's results in fitting the dx line of the life table with 5 skew frequency curves. Plotted from the data of Pearson's original memoir on ‘‘Skew Variation” in Phil. Trans. Roy. Soc. This component, according to Pearson’s graduation, accounted for 484.1 deaths out of the total of 1,000, or nearly one-half of the whole. Its range extends from under 20 years of age to the upper limit of life, at approx- imately 106 years. The second component includes the deaths of middle life. This is the smooth curve having its modal point between 40 and 45 years at the point on the base marked O,. Its range extends from about 5 years of age to about 65. It accounts for 175.2 deaths out of the total of 1,000. It is a long, much spread out 96 BIOLOGY OF DEATH curve, exhibiting great variability. The third compo- nent is made up by the deaths of youth. This accounts for 50.8 deaths out of the total of a thousand, and its range extends from about the time of birth to nearly 45 years. Its mid-point is between 20 and 25 years, and it exhibits less variability than either the middle life or the old age curves. The fourth component, the modal point of which is at the point on the base of the diagram marked O, covers the childhood mortality. It accounts for 46.4 deaths out of the total of 1,000. Its range and variability are obviously less than those of any of the other three components so far considered. The last, excessively skew component, is that which describes the mortality of in- fancy. It is given by a J shaped curve accounting for 245.7 deaths after birth, and an antenatal mortality of 605. In order to get any fit at all for this portion of the mortality curve it is necessary to assume that the deaths in utero and those of the first months after birth are a homogeneous connected group. Summing all these components together it is seen that the resulting smooth curve very closely fits the series of small circles which are the original observations. From the standpoint merely of curve fitting no better result than this could be hoped for. But about its bio- logical significance the case is not quite so clear, as we shall presently see. Pearson himself thinks of these five components of the mortality curve as typifying five Deaths, shooting with different weapons, at different speeds and with dif- fering degrees of precision at the procession of human beings crossing the Bridge of Life. The first Death is, according to Pearson, a marksman of deadly aim, con- centrated fire, and unremitting destructiveness. He kills THE CHANCES OF DEATH 97 before birth as well as after and may be conceived as beating down young lives with the bones of their ances- tors. The second marksman who aims at childhood has an extremely concentrated fire, which may be typified by the machine gun. Only because of the concentration of this fire are we able to pass through it without appal- ling loss. The third marksman Death, who shoots at youth has not a very deadly or accurate weapon, perhaps a bow and arrow. The fire of the fourth marksman is slow, scattered and not very destructive, such as might result from,an old fashioned blunderbuss. The last Death plies a rifle. None escapes his shots. He aims at old age but sometimes hits youth. His unremitting activity makes his toll large. We may let Pearson sum the whole matter up in his own words: ‘‘Our investigations on the mortality statis- tics have thus led us to some very definite conclusions with regard to the chances of death. Instead of seven we have five ages of man, corresponding to the periods of infancy, of childhood, of youth, of maturity or middle age, and of senility or old age. In the case of each of these periods we see a perfectly regular chance distri- bution, centering at a given age, and tailing off on either side according to a perfectly clear mathematical law. . . ‘“‘ Artistically, we no longer think of Death as striking chaotically; we regard his aim as perfectly regular in the mass, if unpredictable in the individual instance. It is no longer the Dance of Death which pictures for us Death carrying off indiscriminately the old and young, the rich and the poor, the toiler and the idler, the babe and its grandsire. We see something quite different, the cohort of a thousand tiny mites starting across the Bridge of Life, and growing in stature as they advance, 7 98 BIOLOGY OF DEATH till at the far end of the bridge we see only the gray- beard and the ‘lean and slippered pantaloon.’ As they pass along the causeway the throng is more and more thinned ; five Deaths are posted at different stages of the route longside the bridge, and with different skewness of aim and different weapons of precision they fire at the human target till none remains to reach the end of the causeway—the limit of life.’’ This whole, somewhat fanciful, conception of Pear- son’s needs a little critical examination. What actually he has done is to get a good empirical fit of the dz line by the use of equations involving all told some 17 con- stants. Because the combined curve fits well, and funda- mentally for no other reason, he implicitly -concludes that the fact that the fit is got by the use of five compo- nents means biologically that the d, line is a compound curve, and indicates a five-fold biological heterogeneity in the material. But it is a very hazardous proceeding to draw biological conclusions of this type from the mere fact that a theoretical mathematical function or functions fits well a series of observational data. I fully discussed this point several years ago and pointed out: ‘“‘The kind of evidence under discussion can at best have but inferential significance; it can never be of de-~ monstrative worth. Itis based on a process of reasoning which assumes a fundamental or necessary relationship to exist between two sets of phenomena because the same curve describes the quantitative relations of both sets. A little consideration indicates that this method of rea- soning certainly cannot be of general application, even though we assume it to be correct in particular cases. The difficulty arises from the fact that the mathematical functions commonly used with adequate results in physi- THE CHANCES OF DEATH 99 cal, chemical, biological, and mathematical investigations are comparatively few in number. The literature of science shows nothing clearer than that the same type of curve frequently serves to describe with complete accuracy the quantitative relations of widely different natural phenomena. As a consequence, any proposition to conclude that two sets of phenomena are causally or in any other way fundamentally related solely because they are described by the same type of curve is of a very doubtful validity.’’ Henderson has put Pearson’s five components together in a single equation, as follows: 7.7525 TLE 0.2215 (t—71.5) —[.05524 (a—41.5)? le wz=15.2( 1— 35 - e + 5.4e — [.09092 (x — 22.5)? +266 +85 (- 2) 3271 2 B27 (@ 3) —5 —. 75 +415.6(2+.75) mney Henderson says regarding this method of Pearson’s for analyzing the life table: ‘‘. . . it is difficult to lay a firm foundation for it, because no analysis of the deaths into natural divisions by causes or otherwise has yet been made such that the totals in the various groups would conform to those frequency curves.’’ The italics in this quotation are the present writer’s for the purpose of em- phasizing the crucial point of the whole matter. Now it is altogether probable that one could get just as good a fit to the observed dz line as is obtained by Pearson’s five components by using a 17 constant equa- tion of the type y=a-t bet cx? + dat+ ext + fat grit ....... + nz's 100 BIOLOGY OF DEATH and in that event one would be quite as fully justified (or really unjustified) in concluding that the d, line was a homogeneous curve as Pearson is in concluding from his five-component fit that it is compound. Indeed Witt- stein’s formula involving but four constants nr n —(M—2) 4 —(me) z= a —a 4 m gives a substantially good fit over the whole range of life. It is, of course, apparent that the formula as here given is in terms of another function, qg,, of the life table, rather than the d. which we have hitherto been discussing. But no difference is in fact involved. gz values may be imme- diately converted into dz values by a simple arithmeti- cal transformation. But in neither Pearson’s, Wittstein’s, nor any other case is the curve-fitting evidence, by and of itself, in any sense a demonstration of the biological homogeneity or heterogeneity of the material. Of far greater impor- tance, and indeed conclusive significance, is the fact, to be brought out in a later chapter, that in material experi- mentally known to be biologically homogeneous, a popu- lation made up of full brothers and sisters out of a brother | x sister mating and kept throughout life in a uniform environment identical for all individuals, one gets a dz line in all its essential features, save for the absence of excessive infant mortality arising from perfectly clear biological causes, identical with the human dz line. It has long been apparent to the thoughtful biologist that there was not the slightest biological reason to suppose that the peculiar sinuosity of the human dz line owed its origin to any fundamental heterogeneity in the material, or differentiation in respect of the forces of mortality. THE CHANCES OF DEATH 101 Now we have experimental proof, to be discussed in a later chapter, that with complete homogeneity of the material, both genetic and environmental, one gets just the same kind of d, line as in normal human material. We must then, I think, come to the conclusion that bril- liant and picturesque as is Pearson’s conception of the five Deaths, actually there is no slightest reason to sup- pose that it represents any biological reality, save in the one respect that his curve fitting demonstrates, as any other equally successful would, that deaths do not occur chaotically in respect of age, but instead in a regular manner capable of representation by a mathematical function of age. An interesting and suggestive analysis of the d, line, resting upon a sounder biological basis than Pearson’s, has lately been given by Arne Fisher. He breaks the curve up into 8 or 9 components, based upon the compar- atively stable values of the death ratios for different groups of diseases characteristic of different ages. The resulting total curve fits the facts from age 10 on, very well, and makes possible the calculation of a complete life table from a knowledge of deaths only. CHAPTER IV THE CAUSES OF DEATH Ir has been suggested in earlier chapters that natural death of the metazoan body may come about fundamen- tally because of the differentiation and consequent mu- tual dependence of structure and function of that body. It is a complex aggregate of cells and tissues, all mutually dependent upon each other and in a delicate state of adjustment and balance. If one organ for any accidental reason, whether internal or external, fails to function normally it upsets this delicate balance, and if normal functioning of the part is not promptly restored, death of the whole organism eventually. results. Furthermore, it is apparent that death does not strike in a haphazard or random manner, but instead in a most orderly way. There are certain periods of life—notably youth—where only an insignificant fraction of those ex- posed to risk ever die. At other ages, as, for example, extreme old age and early infancy, death strikes with appalling precision and frequency. Further we recall with Seneca that nascimus uno modo multis morimur. Truly there are many ways of dying. The fact is obvious enough. But what is the biological meaning of this mul- tiplicity of pathways to the river Styx? There is but one pathway into the world. Why so many to go out? To the consideration of some phases of this problem attention is directed in this chapter. By international agreement among statisticians the causes of human mortality are, for statistical purposes, 102 THE CAUSES OF DEATH 103 rather rigidly defined and separated into something over _180 distinct units. It should be clearly understood that this convention is distinctly and essentially statistical in its nature. In recording the statistics of death the regis- trar is confronted with the absolute necessity of putting every demise into some category or other in respect of its causation. However complex biologically may have béen the train of events leading up to a particular end, the statistician must record the terminal ‘‘cause of death”’ as some particular thing. The International Classifica- tion of the Causes of Death is a code which is the result of many years’ experience and thought. Great as are its defects in certain particulars, it nevertheless has cer- tain marked advantages, the most conspicuous of which is that by its use the vital statistics of different countries of the world are put upon a uniform basis. The several separate causes of death are grouped in the International Classification into fourteen general classes. These are: I. General diseases. II. Diseases of the nervous system and of the organs of special sense. III. Diseases of the circulatory system. 1V. Diseases of the respiratory system. V. Diseases of the digestive system. VI. Non-venereal diseases of the genito-urinary system and annexa. VII. The puerperal state. VIII. Diseases of the skin and of the cellular tissue. IX. Diseases of the bones and organs of locomotion. X. Malformation. XI. Early infancy. ‘XII. Old age. XIII. External causes. XIV. Ill-defined diseases. Perhaps the most outstanding feature which strikes one about the International List is that it is not primarily 104 BIOLOGY OF DEATH a biological classification. Its first group, for example, called ‘‘General Diseases,’’ which caused in 1916 in the Registration Area of the United States approximately one-fourth of all the deaths, is a most curious biological and clinical mélange. It includes such diverse entities as measles and malaria, tetanus and tuberculosis, cancer and gonococcus infection, alcoholism and goiter, and many other unlike causes of death. For the purposes of the statistical registrar it perhaps has useful points to make this ‘‘General Diseases’’ grouping, but it clearly corresponds to nothing natural in the biological world. Again in such parts of the scheme as do have some biological foundation the basis is different in different rubrics. Some have an organological basis, while others have a causational. For purposes of biological analysis, I developed some time ago an entirely different classification of the causes of death, on what appears to be a reasonably consistent basis.* The underlying idea of this new classification was to group all causes of death under the heads of the several organ systems of the body, the functional break- down of which is the immediate or predominant cause of the cessation of life. All except a few of the statistically recognized causes of death in the International Classifi- cation can be assigned places in such a biologically *It should be clearly understood that I am not advocating a new classification of the causes of death for statistical use. I should oppose vigorously any attempt to substitute a new classification (mine or any other) for the International List now in use. Uniformity in statistical classification is essential to usable, practical vital statistics. Such uni- formity has now become well established through the International Classi- fication. It would be most undesirable to make any radical changes in the Classification now. I have made a rearrangement of the causes of death, for the purposes of a specific biological problem, and no other. I am not “proposing a new classification of vital statistics” for official or any other use except the one to which it is here put. THE CAUSES OF DEATH 105 grouped list. It has a sound logical foundation in the fact that, biologically considered, death results because some organ system, or group of organ systems, fails to continue its functions. The headings finally decided upon in the new classi- fication were as follows: I. Circulatory system, blood and blood-forming organs. II. Respiratory system. III. Primary and secondary sex organs. IV. Kidneys and related excretory organs. V. Skeletal and muscular systems. VI. Alimentary tract and associated organs concerned in metabolism. VII. Nervous system and sense organs. VIII. Skin. IX. Endocrinal system. X. All other causes of death. The underlying idea of this rearrangement of the causes of death is to put all those lethal entities together which bring about death because of the functional organic breakdown of the same general organ system. The cause of this functional breakdown may be anything whatever in the range of pathology. It may be due to bacterial infection; it may be due to trophic disturbances; it may be due ta mechanical disturbances which prevent the continuation of normal function; or to any cause what- soever. In other words the basis of the classification is not that of pathological causation, but it is rather that of organological breakdown. We are now looking at the question of death from the standpoint of the biologist, who concerns himself not with what causes a cessation of function, but rather with what part of the organism ceases to function, and therefore causes death. In a series of papers already published I have given a detailed account of this classification, and the reasoning on which particular causes of death are placed in it where 106 BIOLOGY OF DEATH they are. Space is lacking here to go into the details, and I must consequently ask the reader either to take it on faith for the time being that the classification is at least a fairly reasonable one, or to take the trouble to go over it in detail in the original publication.” GENERAL RESULTS OF BIOLOGICALLY CLASSIFIED DEATH RATES Here I should like to present first some general statis- tical results of this classification. The data which we shall first discuss are in the form of death rates, from various causes, per hundred thousand living at all ages, arranged by organ systems primarily concerned in death from specified diseases. The statistics came from three widely separated localities and times, viz., (a) from the Registration Area of the United States; (b) from England and Wales; and (c) from the City of Sao Paulo, Brazil. The summarized results are shown in Table 7, and in graphic form in Figure 26. The rates are arranged in descending order of magni- tude for the United States Registration Area, with the exception of those of group X, all other causes of death. We note in passing that this biologically unclassifiable group includes roughly 10 to 15 per cent of the total mortality. It may be well to digress a moment to con- sider why these deaths cannot be put into our general scheme. Table 8 exhibits the rates included in class X. This residue comprises in general three categories (a) accidental and homicidal deaths; (b) senility; and * Of. particularly Pearl, R. “On the embryological basis of human mortality.” (Proc. Natl. Acad. Sci. Vol. 5, pp. 593-598, 1919) and “ Cer- tain evolutionary aspects of human mortality rates.” (Amer. Natl. Vol. LIV. pp. 5-44, 1920). The following section as well as Chapter V are largely based upon the second of the two papers. THE CAUSES OF DEATH 107 (c) deaths from a variety of causes which are statisti- cally lumped together and cannot be disentangled. Ac- cidental and homicidal deaths find no place in a biologi- TABLE 7 Showing the Relative Importance of Different Organ Systems in Human Mortality Death Rates per 100,000 Group Organ System aad i aes sehen gone —_,_ | Wales 1917 1906-10 | 1901-05 1914 II | Respiratory system ............. 395.7| 460.5) 420.2} 417.5 VI | Alimentary tract and associated OPPONS es ccs ousiane aiaaitane’s gaan 334.9) 340.4] 274.1] 613.8 I | Circulatory system, blood........ 209.8] 196.8} 208.6] 254.8 VII | Nervous system and sense organs .| 175.6| 192.9} 151.9] 124.3 IV | Kidneys and related excretory ORGANS. ii6 5 iinie teere waatioautinnadeas 107.2| 107.4 19.4 83.4 III | Primary and secondary sex organs. 88.1 774 95.4] 103.2 V | Skeletal and muscular system .... 12.6 13.7 18.2 6.8 MILE || USKitts secrac cons cma dacs anecs : 10.1 13.3 12.0 79 IX | Endocrinal system .............. 1.5 1.2 1.9 11 Total death rate classifiable on a biological basis .............. 1,335.5 | 1,408.6 | 1,201.7 | 1,612.8 X | All other causes of death ........ 171.3] 211.8| 141.4] 109.8 cal classification of mortality. A man organically sound in every respect may be instantly killed by being struck by a railroad train or an automobile. The best possible case that could be made out for a biological factor in such deaths would be that contributory carelessness or negli- gence, which is a factor in some portion of accidental deaths, bespeaks a small but definite organic mental in- feriority or weakness, and that, therefore, accidental deaths should be charged against the nervous system. This, however, is obviously not sound. For, in the first place, in many accidents there is no factor of contributory AME YY iii 425 ALIMENTARY § TRACT AND CMM pe ee iii 33.2 CIRCULATORY “209.8 SISTEM LLL. 208.6 BLOOD cnn 2548 patil : 7 VSTEM . a3 Senge”. CED Crees CO HIDNEYS AND = FELATED on £1072 EXCRETORY . ane ORGANS ; : laa AND 68! CONDARY : MM, GIA (SEX ORGANS THT 103.2 SHELETAL AND «126 MUSCULAR " 182 SYSTEM 68 tol SHIN 12.0 79 ENDOCRINAL ve SYSTEM “l US.'REG. AREA 1906-10 ENGLAND ano WALES 1914 SAO FAULO I9IT Fia, 26.—Showing the relative importance of the different organ syatems in human mortality. THE CAUSES OF DEATH 109 negligence in fact, and, in the second place, in those cases where such negligence can fairly be alleged its degree or significance is undeterminable and in many cases surely slight. | Senility as a cause of death is not further classifiable . TABLE 8 All Other Causes N “Cause of Death” as per International ia s i gaeas a Sio 2 lassification Wales | Paulo 906-10 | 1901-05] 1914 | 1917 All external causes (except suicide) 91.9 87.8 26.1 36.4 187, 188 & 189 | Ill-defined diseases.............. 29.4 47.8 7.3 36.3 154. | (Senility : = ‘7 = 1 i ae is } »< oe KR _— & : i— ol pat | a! fb IOS So SEIT BOBS BOS 08 AGE Fra, 33.—Diagram showing the specific rates of death at each age from breakdown of the alimentary tract and associated organs of metabolism (Group VI). .transform the fuel of the human machine into vital energy —ocecur with relatively heavy frequency at all periods of life. These curves are among the few which show av 9 130 BIOLOGY OF DEATH absolutely higher specific force of mortality in infancy than in extreme old age. There is practically no signif- icant difference between the male and female curve at 100 Fi A Vi NERVOUS SYSTEM AND SENSE ORGANS JA 10 A’ nd r S/ : Z $ Ly 7 | g 4 Kh § = 4 ie” iy hs 8g / ; 4 2 fA 7 ws A Nox 1 - a “8 iN 4 w Zee" & Ne a : Ol = — oot : - L O 5 0 I £20 25 30 35 40 45 50 55 60 65 70 75 8) 85 90 95 100 AGE Fie. 34.—Diagram showing the specific death rates at_each age from breakdown of the nervous system and sense organs (Group VII). any portion of life. During early adult life the female curve lies below the male, but by only a small amount. Out of every thousand infants under one, about sixty THE CAUSES OF DEATH 131 die in the first year of life from breakdown of the ali- mentary tract and its associated organs. After the low point, which falls in the relatively early period of 7 to 12 years of age, there is a rapid rise for about ten years in the specific rates of mortality, followed by a slowing off in the rate of increase for the next ten or fifteen years, after which point the curve ascends at a practically uni- form rate until the end of the span of life. Figure 34 shows the trend of the specific mortality from breakdown of the nervous system and sense organs. This organ group, on the whole, functions very well, giv- ing a relatively low rate of mortality until towards the end of middle life. Then the specific rates get fairly large. The low point in this curve is, as in most of the others, at about the time of puberty. From then on to the end of the life span the specific rates increase at a practically uniform rate. The female curve everywhere lies below the male curve except at the extreme upper end of the life span. Before that time, and particularly between the ages of 20 and 50, the business of living evidently either imposes no such heavy demand on the nervous system of the female as it does on that of the male, or else the nervous system of the female is organi- cally sounder than that of the male. The former sug- gestion seems the more probable. That breakdown and failure to function properly, of the skin as an organ system, is a relatively insignificant factor in human mortality, is demonstrated by Figure 35. From a specific death rate of about 1 per thousand in the first year of life it drops abruptly, practically to zero, in early childhood. At about the time of puberty it be- gins to rise again, and ascends at a steady rate during all the remainder of life. The final high point reached 132 BIOLOGY OF DEATH is absolutely low, however, amounting to a specific death rate among those exposed to risk of only a little more than 4 per thousand at the extreme end of life. The female 100 = SKIN 10;— § re W = S a re g He LA = i 9 id / 86 | A => Lif et ZA f ax \ ZF 3 { (_l/ ; | ea, yi z i 4 is , a ! ra yw a 2, = J a? 7 | / LY * (ar; \ y, y \ / (-Xey] | | | ad O 5 1 15 20 25 30 35 40 45 50 55 GO 65 70 7% 80 85 GO 95 100 oe AGE. Fic. 35.—Diagram showing the specific death rates at each age chargeabl gainst the , skin (Group VIII). a eee curve lies well below the male curve practically through- out its course. Deaths from failure to function properly of the organs THE CAUSES OF DEATH 133 of the endocrinal system, including the thyroid gland, suprarenal glands, etc., do not become significant until middle life in the case of the male, as shown in Figure 36, 100 ENDOGRINAL SYSTEM or 8 = Ss in : = 86 ~2 IE ne a & = SF o£ ry x & = gE ’ S | ol Z = q of ~ * a \ Za \ ey : \ J Y a a 4 v e v L ZN 7 “Ty | CN / 1 \ ool_INL 1 A A | © 5 10 IS 20 25 30 35 40 45 50 55 60 65 70 75 80 8&5 90 95 100 AGE Fig, 36.—Diagram showing the specific death rates at each age from breakdown of the endocrinal system (Group IX). although in the female the curve begins to rise from pu- berty on. The specific rates at all ages, of course, are extremely small, practically never rising to more than 134 BIOLOGY OF DEATH 1/10 of one person per thousand exposed to risk. The well-known fact that these glandular organs, whose se- cretions are so important for the normal conditions of 4 — = i] | ALL OTHER CAUSES OF DEATH 100. f 3 v7 8 J S J Su ( (3) 8* / <9 Ff as Zi Bs a ? Ss AAT : ay — “hy 5 v i is) MY, Ke I x Z 7 Wh J iid \ y f \ 7 4 Pad \ a VT ol ! 0 5 0 15 £0 25 30 35 40 45 50 55 60 65 70 75 80 85 90 B5 100 AGE Fia. 37.—Diagram showing the specific death rates from all other causes of death not covered in the preceding categories (Group X). life, are much more unstable and liable to breakdown in the female than in the male, is strikingly shown by this diagram. THE CAUSES OF DEATH 135 Finally, wehavethe diagram for our omnium gatherum group, the ‘‘All other causes of death,’’ in Figure 37. Here we see that, because of accidental and violent deaths, the male specific mortality curve lies far above the female, from youth until old age has set in, about age 75. From that point on to the end of the span of life both curves ascend rapidly together, as a result of the deaths recorded as resulting from senility. Eventually it is to be expected that no deaths will be registered as result- ing from senility. We shall have them all put more nearly where they belong. These diagrams of specific forces of mortality give altogether a remarkably clear and definite picture of how death occurs among men. We see that failure of certain organ systems, such as the lungs, the heart, the kidneys, to maintain their structural and functional integrity, has an overwhelmingly great effect in determining the total rate of mortality as compared with some of the other organ systems. One cannot but be impressed, too, with the essential orderliness of the phenomena we have ex- amined. The probability of any particular organ system breaking down and causing death is mathematically def- inite at each age, and changes in a strikingly orderly manner as age changes, as is shown in Table 11. Thus we find that in the first year of life it is the alimentary tract and its associated organs which most frequently break down and cause death. From age 1 to age 60 the specific force of mortality from breakdown of the respiratory system is higher (with a few insignificant exceptions in the females) usually by a considerable amount, than that associated with any other organ system of the body. From 60 to 90 years of age the circulatory 136 BIOLOGY OF DEATH system takes the front rank, with a higher specific mor- tality rate than any other organ system. TABLE 11 The most fatal organ systems at different ages MALES FEMALES te Gents of all en ane ok all jologically Age 1ologically Pope ie aS goneenedie Luce Group est oa 6 Tepe ae ae breakdown of proportion proportion breakdown of specified organ of fatalities of fatalities specified organ system system 68.8 Alimentary tract o— 1 Alimentary tract 40.6 50.1 Respiratory 1— 4 Respiratory 51.3 41.2 Respiratory 5— 9 Respiratory 42.5 27.1 Respiratory 10—14 Respiratory 33.3 43.6 Respiratory 15—19 Respiratory 43.8 52.6 Respiratory 20—24 Respiratory 46.0 49.7 Respiratory 25—29 Respiratory 44.2 45.6 Respiratory 30—34 Respiratory 39.5 39.9 Respiratory 35—39 Respiratory 33.2 33.3 Respiratory 40—44 Respiratory 27.5 28.0 Respiratory 45—49 Respiratory 22.1 23.6 Respiratory 50—54 Alimentary tract 21.6 25.0 Circulatory 55—59 Alimentary tract 22.6 28.4 Circulatory 60—64 Circulatory 24.4 30.9 Circulatory 65—69 Circulatory 25.6 32.5 Circulatory 70—74 Circulatory 28.0 32.9 Circulatory 75—79 Circulatory 28.4 33.3 Circulatory 80—84 Circulatory 30.4 85—89 Circulatory 30.8 If our lungs were as organically good relatively as our hearts, having regard in each case for the work the organ is called upon to do and the conditions under which it must do it, we should live a considerable number of years longer on the average than we do now. One cannot but feel that the working out of a rational and scientifi- cally grounded system of personal hygiene of the respir- THE CAUSES OF DEATH 137 atory organs, on the broadest basis, to include all such matters as ventilation of buildings, etc., and the putting of such a personal hygiene into general use through education, would pay about as large dividends as could be hoped for from any investment in public health secu- rities. I am aware that much has already been done in this direction, but in order to reap any such dividends as I am thinking of, a vast amount must be added to our present knowledge of the physiology, pathology, epidemi- ology, and every other aspect of the functions and struc- tures of respiration. CHAPTER V EMBRYOLOGY AND HUMAN MORTALITY In the preceding chapter attention was confined strictly to the organological incidence of death. It is possible to push the matter of human mortality still farther back. In the embryological development of the vertebrate body, there are laid down at an early stage, in fact immediately following the process of gastrulation, three morphologically definite primitive tissue elements, called respectively the ectoderm, the mesoderm and the endoderm. These are termed the germ-layers, and em- bryological science has, for a great many forms, succeeded in a broad way in tracing back to the primitive germ layer from which it originally started its development, substantially every one of the adult organs and organ systems of the body. Itmakes no difference to the validity or significance of thediscussion which we are about to enter upon, in what degree of esteem or contempt in biological philosophy the germ layer theory or doctrine, which oc- cupied so large a place in morphological speculation 50 years ago, may be held. We are here concerned only with the well-established broad descriptive fact, that in general all adult organ systems may be traced back over the path of their embryological development to the germ layer, or combination of germ layers, from which they origin- ally started. Having arranged, so far as possible, all causes of death on an organological basis, it occurred to me to go one 138 EMBRYOLOGY AND HUMAN MORTALITY 139 step further back and combine them under the headings of the primary germ layers from which the several organs developed embryologically. To do this was a task of considerable difficulty. It raised intricate, and in some TABLE 12 Showing the relative influence of the primary germ layers in human mortality (Items 64 and 65 charged to ectoderm) Death rate per 100,000 due to functional breakdown of organs embryologically developing from Locality Ecto- Per Meso- Per Endo- Per derm cent. derm cent. derm cent. United States Registration Area, 1906-10.......... 191.1] 14.8 | 425.2] 31.8 | 719.6) 53.9 United States Registration Area, 1901-05.......... 210.6] 15.0 | 407.1] 29.0 | 786.2] 56.0 England and Wales, 1914...) 177.1] 14.4 | 374.0] 30.3 | 681.5] 55.3 Sao Paulo, 1917 ........... 134.9| 8.4 | 468.0] 29.0 |1009.9| 62.6 TABLE 13 Showing the relative influence of the primary germ layers in human mortality (Items 64 and 65 charged to mesoderm) Death rate per 100,000 due to functional breakdown of organs embryologically developing from Locality Ecto- Per Meso- Per Endo- Per derm cent. derm cent. derm cent. United States Registration Area, 1906-10.......... 116.9] 8.7 | 499.4] 37.4 | 719.6] 53.9 United States Registration Area, 1901-05.......... 187.3] 9.8 | 480.4] 34.2 | 786.2] 56.0 England and Wales, 1914...] 107.9] 6.7 | 443.2] 36.0 | 681.5} 55.3 Sao Paulo, 1917 ........... 101.3; 6.3 | 501.6} 31.1 |1009.9| 62.6 cases still unsettled, questions of embryology. Further- more, the original statistical rubrics under which the data are compiled by registrars of vital statistics were never planned with such an object as this in mind. Still the thing seemed worth trying because of the biological interest which would attach to the result, even though it were some- 140 BIOLOGY OF DEATH what crude and, in respect of minor and insignificant details, open to criticism. It is not possible here to go into details as to how the causes of death were combined in WE M4 YUE US. REGISTRATION AREA 1906-10 VSI ENGLAND and WALES i9l4& 62.6 YK£5G7; sae YRWUG 4 tN : 10 = oO B 5 1 16 20 26 30 2640 45 GO BS OO GS 7015 BOBS BO OF AGE Fig. 41.—Showing survival curves of members of the Hyde family (Plotted from Bell’s data). beginning at age 15 and continuing to age 90, the female curve lies below that for the males, whereas normally for the general population it lies above it. This denotes a shorter average duration of life in the females than in the males, the actual figures being 35.8 years for the males and 33.4 years for the females. Bell attributes the dif- ference to the strain of child-bearing by the females in 154 BIOLOGY OF DEATH this rather highly fertile group of people, belonging in the main to a period when restrictions upon size of family were less common and less extensive than now. In the second place, the female J, curve is actually convex to the base throughout a considerable portion of middle life whereas, normally, this portion of the curve presents a concave face to the base. Apart from these deviations, which are of no partic- ular significance for the use which Bell makes of the data, the Hyde material is essentially normal and simi- lar to what one would expect to find in a random sample of the general population. In this material there were 2,287 cases in which the ages at death of the persons and the ages at death of their fathers were known. It occurred to Bell to arrange this material in such a way as to show what, if any, relation existed between age at death of the parent and that of the offspring. He arranged the parents into four groups, according to the age at which they died, and the offspring into five groups upon the same basis. In the case of the parents the groups were: First, those dying under 40; second, between 40 and 60; third, between 60 and 80; and fourth, at age 80 and over. The groups for the offspring were the same, except that the first was divided into two parts, namely, those dying under 20 and those dying between 20 and 40. The result- ing figures are exhibited in Table 14. The results for father and offspring are shown in Figure 42, based upon the data of Table 14. In each of the 5 polygons, one for each offspring group, the first dot shows the percentage of fathers dying under 40; the second dot the percentage of fathers dying between 40 and 60; and so on, the last dot in each curve showing the percentage of fathers dying at age 80 and over. It THE INHERITANCE OF DURATION TABLE 14 Analysis of the Hyde family data by person’s age at death, showing the number and percentage having (a) fathers and (b) mothers who died 155 at the age periods named. (From Bell) Father's age at death Person’s age at death Stated -40 40-60 60-80 80+ Pretec scp nares Oe aie Seuss Vaaraiataas 2,287 66 522 1,056 643 Under 20.0... 000.00 cece eee es - 669 20 189 299 161 20 and under 40.......... phe acunaee 538 18 140 269 111i 40 and under 60..................... 467 12 116 215 124 60 and under 80..................... 428 13 57 .196 162 80 and over..................000000- 185 3 20 77 85 Percentages Stated eh esieerduasdaueeecied: 100.0 2.9 22.8 46.2 28.1 Under 20 ....... 0... ccc eee eee ee 100.0 3.0 28.2 44.7 24.1 20 and under 40..................... 100.0 3.4 26.0 50.0 20.6 40 and under 60..................... 100.0 2.6 248 46.0 26.6 60 and under 80..................00. 100.0 3.0 133 45.8 37.5 80 and over. .............. 0c cee eee 100.0 16 108 41.6 46.0 Mother's age at death Person's age at death Stated -40 40-60 60-80 80+ Sta tedisage vamamicmedsax besa sd eenieared 1,805 191 4385 713 466 Winder 0 dsc ibe ever laew 511 88-129 199 «95 20 and under 40................0 000 407 42 104 176 85 40 and under 60.................005- 379 27 92 159 101 60 and under 80..................00, 360 26 80 129 125 80 and over... 0... 6. cece eee 148 8 30 50 60 Percentages Stated eoecasuins dno eavaravncgen coe mes 100.0 10.6 24.1 39.5 25.8 Undert20 is scke tee eis anne vam cea narns 100.0 172 25.2 39.0 186 20 and under 40........0..........04. 100.0 10.3 256 48.2 20.9 40 and under 60..................... 100.0 7.1 243 42.0 26.6 60 and under 80..................... 100.0 7.2 22.2 35.9 34.7 80 and over...........0. cece cece cues 100.0 54 203 338 40.5 156 BIOLOGY OF DEATH is to these last dots that attention should be particularly directed. It will be noted that the dotted line connecting the last dots of each of the 5 polygons in general rises as we pass from the left-hand side of the diagram to the right-hand side. In the case of offspring dying under 20, 24 per cent. of their fathers died at ages over 80. About 50 50 40 40 90 50 20 20 - 40 60 8 -—- 40 60 8 - 40 60 80 - 40 60 86 - 40 60 60 40 60 60 + 40 60 8 + 40 60 80 + 40 60 80 + 40 60 & + Fig. 42.—Influence of father’s age at death upon longevity of offspring. First dot in each diagram shows the percentage having fathers who died at 40; second dot the percent- age having fathers who died from 40-60; third dot the percentage having fathers who died from 60-80; fourth dot the percentage having fathers who died 80+ (After Bell). 21 per cent. of the fathers of offspring dying between 20 and 40 lived to be 80 years or over. For the next longer- lived group of offspring, dying between 40 and 60, the percentage of fathers living to 80 or over rose to 27 per cent. In the next higher group, the percentage is nearly 38, and finally the extremely long-lived group of offspring, the 185 persons who died at ages of 80 and over, had 46 per cent. or nearly one-half of their fathers living to the same great age. In other words, we see in general that the longer-lived a group of offspring is, on the average, the longer-lived are their fathers, on the average; or, put in another way, the higher the percentage of very THE INHERITANCE OF DURATION 157 long-lived fathers which this group will have as com- pared with shorter-lived individuals. Figure 43 shows the same sort of data for mothers and offspring. Here we see the curve of great longevity of parents rising in an even more marked manner than was the case with fathers of offspring. The group of oN 407 379 360 148 PERSONS PERSONS PERSONS PERSONS PERSONS DIED DIED DIED DIED DIED -20 20-40 40-60 60-80 60+ 50 50 40 40 30 30 20 Fie, 43.—Influeace of mother’s age at death upon longevity of offspring. First dot in each diagram shows the percentage having mothers who died at 40; second dot the per- centage having mothers who died at 40-60; third dot the percentage having mothers who died 60-80; fourth dot the percentage having mothers who died 80+ (After Bell). offspring dying at ages under 20 had only 19 per cent. of their mothers living to 80 and over, whereas the group of offspring who livéd to 80 and beyond had 41 per cent. of their mothers attaining the same great age. At the same time we note from the dotted line at the bot- tom of the chart that as the average age at death of the offspring increases, the percentage of mothers dying at early ages, namely, under 40, as given by the first dots, steadily decreases from 17 per cent. at the first group to just over 5 per cent. for the offspring dying at very advanced ages. 158 BIOLOGY OF DEATH These striking results demonstrate at once that there is a definite and close connection between the average longevity of parents and that of their children. Hx- tremely long-lived children have a much higher percent- age of extremely long-lived parents than do shorter lived children. While the diagrams demonstrate the fact of this connection, they do not measure its intensity with as great precision as can be obtained by other methods of dealing with the data. A little farther on we shall take up the consideration of this more precise method of measurement of the hereditary influence in respect of longevity. In the preceding diagrams we have considered each parent separately in connection with the offspring in TABLE 15 Longevity of parents of persons dying at 80 and over. (From Bell) Number of Per cent. of Age at death of parents Number of persons lived persons lived persons 80+ SN 1,594 139 8.7 Lived to be 80+ Neither parent............. 827 44 5.3 One parent (not other) ...... 583 57 9.8 Both parents............... 184 38 20.6 Father (not mother) ........ 337 38 11.3 Mother (not father)......... 246 19 7.7 regard to longevity. We shall, of course, get precisely the same kind of result if we consider both parents to- gether. For the sake of simplicity, taking only the cases of extreme longevity, namely, persons living to 80 or over—the essential data are given in Table 15. From this table it is seen that where neither parent lived to be 80, only 5.3 per cent. of the offspring lived to be 80 or over, the percentage being based upon 827 THE INHERITANCE OF DURATION 159 cases. Where one parent, but not the other, lived to be 80 or older, 9.8 per cent. of the offspring lived to be 80 or older, the percentage here being based upon 583 cases. Where both parents lived to be 80 or older 20.6 per cent. of the persons lived to the same great age, the percentage be- ing based upon 184 cases. Thus it appears that in this group of people four times as many attained great longev- ity if both their parents lived to an advanced age, as attained this age when neither parent exhibited great longevity. The figures from the Hyde family seem fur- ther to indicate that the tendency of longevity is inherited more strongly through the father than through the mother. Where the father, but not the mother, lived to be 80 or older, 11.3 per cent. of the persons lived to age 80 or more, there being 337 cases of this kind. Where the mother, but not the father lived to be 80 or older, only 7.7 per cent., or nearly 4 per cent. fewer of the persons lived to the advanced age of 80 or more, there being 246 cases of this sort. Too much stress is not, however, to be laid upon this parental difference because the samples after all are quite small. One other point in this table deserves consideration. Out of the 1,594 cases as a whole, less than 9 per cent. of the persons lived to the advanced age of 80 or more. But out of this number there are 767, or 48.1 per cent., nearly one-half of the whole, who had parents who lived to 80 or more years. Another interesting and significant way in which one may see the great influence of the age of the parents at death upon the longevity of the offspring, is indicated in Table 16, where we have the average duration of life of individuals whose fathers and mothers died at the specified ages. 160 BIOLOGY OF DEATH We see that the longest average duration of life, or expectation of life, was of that group which had both mothers and fathers living to age 80 and over. The average duration of life of these persons was 52.7 years. Contrast this with the average duration of life of those whose parents both died under 60 years of age, where TABLE 16 Showing the influence of a considerable degree of longevity in both father and mother upon the expectation of life of the offspring. (After Beli). (In each cell of the table the open figure is the average duration of life of the offspring and the bracketed figure is the number of cases upon which the average is based). Mother’s age at death Father’s age at death Under 60 60-80 Over 80 Under 60 32.8 years 33.4 years 36.3 years (128) (120) (74) 60-80 35.8 38.0 45.0 (251) (328) (172) Over 80 42.3 45.5 52.7 (131) (206) (184) the figure is 32.8 years. In other words, it added al- most exactly 20 years to the average life of the first group of people to have extremely long-lived parents, instead of parents dying under age 60. In each column of the table the average duration of life advances as we proceed from top to bottom—that is, as the father’s age at death increases—and in each row of the table the aver- age expectation of life of the offspring increases as we pass from left to right—that is, with increasing age of the mother at death. However the matter is taken, a careful selection of one’s parents in respect of longevity is the most reliable form of personal life insurance. THE INHERITANCE OF DURATION 161 How great and deep is the significance of the facts shown in Table 16 may best be brought home to the mind by means of a comparison. Suppose this question to be asked: by how great an amount would the average expectation of life at birth (which in a stable population is the same thing as the mean duration of life) be increased if all the reasonably preventable deaths were prevented? If, say 75 per cent. of all the deaths from pulmonary tuber- culosis did not occur; if 40 per cent. of the deaths from Bright’s disease were prevented; and, in general, if all that medicine and hygiene knows today were put into reasonably effective operation, and nobody died except when and from such causes as could in no way be influenced by what medical science, good envi- ronment, etc., have to offer: by how much then would the expectation of life be greater than it now is? We have seen that, to have one’s parents live to 80 or over increases the expectation of life 20 years, as compared with that of persons whose parents die under 60 years of age. By how much more would the expectation of life be extended if all reasonably preventable deaths were prevented? A thorough and critical answer to this question is afforded by an investigation of Forsyth’s, conducted along the most exact and approved actuarial lines. Some years ago, Professor Irving Fisher sent a list of some 90 diseases to a group of the most prominent medi- cal authorities in this country, and asked them to desig- nate what percentage of the deaths due to each disease they considered preventable. The results of this inquiry were tabulated in an extremely conservative manner, with the result set forth in Table 16a, which is copied from Forsyth’s paper(pp. 762-763). 11 162 BIOLOGY OF DEATH TABLE 16a Showing Fisher’s ratios of preventability for the diseases enumerated in the mortality statistics of the United States, together with the relative importance of each disease as indicated by the percentage the number of its deaths bears to the total number of deaths Prominence of Ratio of Causes of death disease. Percent.| preventability. of all deaths Per cent. 1 Premature birthe..s504 4005 tener eee vnceweoeny 2.0 40 2 Congenital malformation of the heart .......... 55 0 3 Other congenital malformations ............... 3 0 4 Congenital debility................... 000 2.3 40 5 Hydrocephalus ............ cece eee e eee eee ak: (0) 6 Venereal diseases 3 70 7 Diarrhea and enteritis 7.74 60 SB) Mieaslep iaiicsnciscacsderosce st onan gaiinealonie dara 8 40 9 Acute bronchitis .......... 0.0.0: sce e rece enee 1.1 30 10 Bronchopneumonia..............-.-2+eeeeeee 2.4 50 11 Whooping cough .............. 02 cece cece 9 40 12: Croup escccvcseensnese eee eek. Remora eyes 3 75 TS MCBISEG cn nsinw wis civn deepens iaciadonwene 1.6 70 14 Diseases of larynx—not laryngitis.............. 07 40 15) Vary ngitie sis cnediecsiexewsdweaa a aaanaw end .06 40 16> Diphtheria sii. vic ccuesiaiscanncaienisedee cas 1.4 70 17 Scarlet feveriiesiicccciiie dive o's psec Ba esvemman wares 5 50 18 Diseases of lymphatics..................0000e .O1 20 419 Donilbiesuscceeser eens eas eeeon vee rane sens .05 45 20° Tetanns) i. cei niwers camens tgeage ne anacemewsen .19 80 21 Tuberculosis—not of lungs.................... 17 15 LDS SCORE yas 16 ac5ia:by se ek ond sere ore so saocilares sunieuerdueedvover ayaa .08 60 23 Appendicitis............. cee ee cee eee eee .7 50 24: Typhoid fevertivisaicia ie wetend caduan ainyeoinlead 2.0 85 25 Puerperal convulsions ..................0000- .2 30 26 Puerperal septicemia ...............-.000 005 4 85 27 Other diseases of childbirth. .................. .36 50 28 Diseases of tubes............--.. 02 e eee eee 1 65 29) Peritonitis: sic caseussa viene ayes ead edanc te 6 55 80 Smallpox: civccisccs eis eo dead we cued eens .O1 75 31 Tuberculosis of lungs................. Pita 9.9 75 BO) VAGOLEN 66 os eisai oacinere raison Mab Arace een watlansulaies 7.5 35 OS Moalarial lovers sccvasnsceceiansawa va viewwuawea 2 80 SE: Beptiow mia yieis:c cic csv ci ceseaieiats Vaew wee suncciaraks ayers 3 40 35! “Bpilepe yi cine scsccarcatesarsiae saw eumanemusane .29 (1) 36 General, ill-defined, and unknown causes (in- cluding “heart failure,’ “dropsy,’”’ and ‘‘con- Vulaions") cexsascahavaacsb hep chiwta vere 9.2 30 Bl BPSD as: jose s:cis oss ccaie Saveceracdvacsiaceceatiwieronas- bean 3 60 38 Pneumonia (lobar and unqualified) 7.0 45 39 Acute nephritis o.cc ccc ccs cacntawsawcuee cape 6 30 AO) “PlOUripy, :a.sis-siassaseisseiasts,stlgngsnls adress stevesiaielerg eeega .27 55 41 Acute yellow atrophy of liver .....,........... .02 (1) 42 Obstructions of intestines...................0. .6 25 THE INHERITANCE OF DURATION 163 TABLE 16a—Continued Prominence of Ratio of Causes of death disease. Percent. | preventability. of all deaths Per cent. 43. Aleoholismiveicis s csseaaceaweinacnd cae sieis one A 85 44 Hemorrhage of lungs .............sceceeveees os 80 45 Diseases of the thyroid body................65 .02 10 46 Ovarian tumor..............00e0es pisecae -07 (t) 47 Uterine tumor 9:66 vices a oe eeceie a tee etoa’e os ok 60 48 Rhoumatism sic cs sicesiess ssnweasseannes eevawy 5 10 49 Gangrene of lungs.........0. cc cceeeeeeeeeees .03 0 50 Anmmia, leukwmia ......... 2... cece 4 50 51 Chronic poisonings ...........0 0c eee cece en ee -05 70 52 Congestion of lungs..........0.cceceeeeeeeees 4 50 53 Ulcer of stomach........6.. cece eeeeeneee avast 2 50 Be, Osrbaneles «sc. . vanaug ssagarde piece iawwes .03 50 BS Peridarditituces + pxayau eeeaners coe eues paaeeee 1 10 56 Cuncer of female genital organs............... 6 0 50 Dyseatery: iss: sce spavice tawiien iaeie Shea ) 80 BR SARE ine cherie osaeesasdeandess dasaae -65 50 59 Cholera nostras.......... cece csc ee reenenence -09 50 60 Cirrhosis of liver .............05 iesan ade esiiaoeneve 9 60 61 General paralysis of insane..............0.000s 3 75 62 Hyatid tumors of liver ........... 00. cece wees -002 75 63 Endocarditia s«isunees vcenness vanes ceweevay 8 25 64 Locomotor ataxia............ 0. ese e een e neces 17 35 65 Diseases of veins 04 40 66 Cancer of breast......... LPPAG Pe RA Ae RER 4 0 G7 Diabetes. cise ovis wveyescc se aaserbis estwareie catalase anne 8 10 GB. Biliary calo uli cissisiecs'o saa aisialts sage sieves gis ngyaie’ . 17 40 GO Ferns cies y 2 tee ee Rees deena Bees 27 70 70 Cancer not specified ........... cece were ee eeee a) 0 Tl TUMmor ss. 0 2 keaavees cameiees sows ae iawien 0% .08 0 72 Bright's disease........... ccc eee e eee cece eens 5.6 40 73 Embolism and thrombosis.......... estat valk tee 26 0 74 Cancer of intestines............... 0c cece eens .55 0 75 Cancer of stomach and liver.................4. 1.7 (1) 76 Calculi of urinary tract ...........20eeeeeeees .03 10 77 Cancer of mouth .......... 6. eee e cece es en eves el 0 7S Peart discast.,... 2-2. 26acde oe detas dcawcgictis 8.1 25 79: Tape th Beh so cae: eae aioston inecace’ ga sauah 19 ow: #iettetn, afd e/acaen 7 50 80 Asthma and emphysema............+sseseeees .23 30 81 Angina pectoris ......... 0s cece cee e tence neues A 25 OS APODlOS iis uss sh twee ee ee eres eee ends Hid 4.4 35 83 Cancer of skin..........cccce sectors eseceees .2 0 84 Chronic bronchitis .......... 0. cece eee e ae eens 8 30° 85 Peralysitcncevsascekasdciaeniin reese wee ed 1.0 50 86 Softening of brain........... cece cece eee e eens .2 Ct) 87 Diseases of arteries... .......cceseeceeseeecees .83 10 88 Diseases of bladder............ ae eR 2 45 89 Gangrene ..........ceeeceer eee eiiaeree BSS 25 60 90 Old age........eeeeerereene fire tia eae aibie Bisadaens 2.0 (1) 164 BIOLOGY OF DEATH It will be seen that these ratios of preventability are not all 100 per cent. They are not the wild overstate- ments of the propagandist. But they do. represent, if they could be realized, substantial reductions from exist- ing mortality rates. TABLE 16b Complete expectations of life as based upon the two assumptions that deaths are and are not prevented according to the ratios given in Table 16a Deaths Loss in Deaths Loss in Age Age k ee ia Beast Years| Days abe Bn Years | Days Obra grateteaiaciere 49.44 | 62.11 12 245 | 25......... 39.31 | 46.18 6 318 Veasrs yee 56.03 | 66.26 10 BE, | QB. ieee cece 38.56 | 45.31 6 274 Dxeren este 56.84 | 66.28 9 VG. | 2s senses esas 37.82 | 44.45 6 230 Dvistacatein ite tee 56.64 | 65.67 9 Tl | 28.065 2e ses 37.08 | 43.58 6 183 Bs soosinithayiece 56.15 | 64.94 8 288 | 29......... 36.34 | 42.72 6 139 i eee cnvesia saver: 55.51 | 64.13 8 226 | 30......... 35.61 | 41.86 6 91 GD naar eaenieaee 54.81 | 63.27 8 168 | 31......... 34.88 | 41.01 6 47 [ee ee 54.06 | 62.42 8 131 | 32......... 34.15 | 40.15 6 0 B nraavsierdivae 53.26 | 61.54 8 OQ: | BS .icsaiediecs 33.42 | 39.30 5 321 Dens-sverianeans 52.43 | 60.63 8 1B | B4vscien eens 32.69 | 38.46 5 281 lOsceaxeewes 51.57 | 59.72 8 65.) Bbje. cerns 31.96 | 37.61 5 237 Laine 50.69 | 58.79 8 BF | BGs en eas 31.23 | 36.76 5 193 1D, cic oe 49.80 | 57.86 8 22. | Shia new aves 30.50 | 35.92 5 153 MB eicsadieneiese 48.91 | 56.80 7 B21. | BBoo cscs 29.77 | 35.08 5 113 V4 i ccteeangies. 48.03 | 56.00 7 354 | 39......... 29.03 | 34.24 5 V7 Wiviccinarorass 47.15 | 55.07 7 336 | 40......... 28.30 | 33.40 5 37 UG us cacs secenrrera 46.31 | 54.16 7 310 | 41......... 27.57 | 32.57 5 0 Me esiasgucssanaeras 45.50 | 53.26 7 QT | BQ wicca: 26.85 | 31.74 4 325 WSiscnciadsianscs 44.71 | 52.36 7 237 | 43......... 26.12 | 30.91 4 288 1Qciarawte 43.93 | 51.48 7 201 | 44......... 25.40 | 30.09 4 252 20 c/ooe eee 43.15 | 50.59 7 161 | 45......... 24.68 | 29.28 4 219 DQ icssceiarsieanse? 42.37 | 49.70 7 120) | 463¢caeeens 23.97 | 28.47 4 183 DD cca isenise aioe 41.60 | 48.82 Ch BO | AT ucersicisiaww's 23.26 | 27.67 4 150 28 sire ie aceha® 40.83 | 47.94 7 40 | 48......... 22.56 | 26.87 4 113 pi eee 40.07 | 47.06 6 261. AD nese 21.87 | 26.09 4 80 On the basis of the mortality experience of the Regis- tration Area for 11 years (1900-1910) Forsyth calculated mortality tables on the assumption that the ratios of preventability of Table 16a were actually in full opera- tion. The results, so far as concerns expectation of life, are set forth in Table 16b. THE INHERITANCE OF DURATION 165 From the first line of this table it is perceived that the total increase in expectation of life which would result if Fisher’s ratios of preventability were fully realized is just under 13 years! How unfavorably this contrasts with the 20 years increase shown by the two TABLE 16b—Continued Deaths Loss in Deaths Loss in Age Age eae | vented Years} Days eee Besar Years | Days SO icccaiies ve 21.17 | 25.30 4 BT I Teictsrarsianss 8.82 | 11.15 2 120 ip eer ete 20.47 | 24.52 4 VS) PP Quaieespeeries 8.36 | 10.59 2 84 Owen seaee 19.78 | 23.74 3 350 | 73......... 7.93 | 10.04 2 40 GS nie seas 19.09 | 22.97 3 321 | 74......... 7.50 9.51 2 4 OB eee cieiesare 18.40 | 22.21 3 296 | 75......... 7.09 8.99 1 329 OD saigaciareeaee 17.74 | 21.46 3 263 | 76......... 6.70 8.49 1 288 (): eee 17.08 | 20.72 3 BS 4e | UP Pes sescasea ae 6.31 8.00 1 252 BU seis foes 16.45 | 20.00 3 POL | TB sc aspen 5.98 7.53 1 201 G8 vesisivic wees 15.83 | 19.30 3 193 | 790 eeivne 5.64 7.07 1 157 DOs iiecoxens 15.23 | 18.61 3 139 | 80......... 5.32 6.63 1 113 COs ipesistig ses 14.63 | 17.93 3 DLO: } SLsieic.siecd «2 5.02 6.20 1 66 (i) ee eee 14.05 | 17.27 3 80 | 82......... 4,74 5.78 1 15 (nee 13.48 | 16.61 3 AE BSB aicksecane 4.47 5.38 332 OB i ccsiere sceenavs 12.92 | 15.96 3 15 | 84......... 4.23 4.99 277 GE vores bcd eiets 12.36 | 15.32 2 350 | 85......... 4.01 4.62 223 65 cccesecaxs 11.82 | 14.69 2 348 | 86......... 3.79 4.25 168 6G. shag 11.29 | 14.07 2 285 | 87......... 3.58 3.89 113 GT ia casei epeicotevens 10.77 | 13.47 2 256 | 88......... 3.39 3.56 62 (i): eee eee 10.26 | 12.87 2 223 | 89........- 3.22 3.27 18 Cis cisscscics 9.77 | 12.29 2 190 | 90......... 3.06 3.06 0 (ie escecees 9.29 | 11.71 2 153 corner diagonal cells of Table 16! No more striking demonstration could be found of the overwhelming im- portance of heredity in determining duration of life. For if all the deaths which reason will justify one in suppos- ing preventable on the basis of what is now known, were prevented in fact the resulting increase in expectation of life falls seven years short of what might reasonably be expected to follow the selection of only one generation of ancestry (the parental) for longevity. So much for Bell’s analysis of longevity in the Hyde 166 BIOLOGY OF DEATH family. We have seen that it demonstrates with the ut- most clearness and certainty that there is an hereditary influence between parent and offspring affecting the ex- pectation of longevity of the latter. Bell’s method of handling the material does not provide any precise meas- ure of the intensity of this hereditary influence, nor does it furnish any indication of its strength in any but the direct line of descent. Of course, if heredity is a factor in the determination of longevity we should expect its effects to be manifested as between brothers and sisters, or in the avuncular relationships, and in greater or less degree in all the other collateral and more remote direct degrees of kinship. Happily, we have a painstaking analysis, with a quantitative measure of the relative in- fluence of heredity in the determination of longevity, which was carried out many years before Bell’s work on the Hyde family, by the pioneer in this field, Prof. Karl Pearson. His demonstration of the inheritance of longev- ity appeared more than twenty years before that of Bell. I have called attention to the latter’s work first merely because of the greater simplicity and directness of his demonstration. We may now turn to a consideration of Pearson’s more detailed results. PEARSON’S WORK The material used by Pearson and his student, Miss Beeton, who worked with him on the problem, came from a number of different sources. Their first study dealt with three series from which all deaths recorded as due to accident were excluded. The first series included one thousand cases of the ages of fathers and sons at death, the latter being over 22.5 years of age, taken THE INHERITANCE OF DURATION 167 from Foster’s ‘‘Peerage.’? The second series consisted of a thousand pairs of fathers and sons, the latter dying beyond the age of 20, taken from Burke’s ‘Handed Gentry.’? The third series consisted of ages at death of one thousand pairs of brothers dying beyond the age of 20 taken from the ‘‘Peerage.’’ It will be noted that all these series considered in this first study dealt only with inheritance in the male line. The reason for this was simply that in such books of record as the ‘‘Peerage’’ and ‘‘Landed Gentry”’ sufficiently ex- act account is not given of the deaths of female relatives. In a second study the material was taken from the pedi- gree records of members of the English Society of Friends and from the Friends’ Provident Association. This ma- terial included data on inheritance of longevity in the female line and also provided data for deaths of infants, which were lacking in the earlier used material. The investigation was grounded upon that important branch of modern statistical calculus known as the method of correlation. For each pair of relatives between whom it was desired to study the intensity of inheritance of longe- vity a table of double entry was formed, like the one shown here as Table 17. The figures in each cell or compartment of this table denote the frequency of occurrence of pairs of fathers and adult sons having respectively the durations of life indicated by the figures in the margins. Thus we see, examining the first line of the table, that there were 11 cases in which the average duration of life of the father was 48 years and that of the adult son 23 years. Farther down and to the right in the table there were 13 cases in which the average duration of life of the father and the son was in each case 83 years. These cases are men- 168 BIOLOGY OF DEATH tioned merely as illustrations. The whole table is to be read in the same manner. From such a table as this it is possible to calculate, by well-known mathematical methods, a single numerical constant of somewhat unique properties known as the TABLE 17 Correlation table showing the correlation between father and son in respect of duration of life DURATION OF LIFE OF FATHER | 23|28|33/38/43/48153] 58] 63] 68| 73| 78| 83| 88/ 93/ 98/103)/Totals 23| 1] 1) 2| 5] alti] 6! z| 11/ 9| 6] 12; 8| 2 2 86 - B 1| 6| 4/ 5] 12] 15] 10] 13| 10| 7 i) i 85 Z 33 1] 2] 2/ 5} 7} 8} 7 iol 7 si} s| 4] 4 70 2 38 1/2) | 2/8] 5] 3} 9} ail ail of a] 2] 1 70 & 43l | 1 1] 5| 1) 5} 6| 11) 10] 10} 17] 5 72 48 1] 1] 2] 5] 5} 4} 6] 9] 12] 15] 5] 3 68 B 531 | a) | 3i | 5| 7 3} 2] a] ai 14} 10) 1] a} 1 70 A 58 1 3 | 4} 5] 10] 8] 10) 5| 8] 9] 3 2 68 & 63} | 2| 1] 3] 5] a] 4] 8} 13) 9/ 14) 11] 11) 5 84 , «88 1] 6| 3| 6| 7} 5} 5| 6] 14| 16] 12) 7] 2 90 S 73; | 1) | 2} 1) 6 5} 4] 7| 9} 10] 14] 13] 8} 8} 1) a] 90 E 78 1] 1] 2] 2] 4] 4} 4/10] 5] 8} 9] 4 3 57 3 83 1] 1] 5} 3] 1} 2] 3) 7] 10] 13) 3] 2) 2 53 B gg} | 1 2| 3 1] 4| 7 5] a 2 2 28 93 1 al 2 5 98 1 1 1] 1 4 Totals| 1! 8! 9l3ol26lesi7ol 76! 9ol122!131/1531132! 53l isl 151 1! 1000 coefficient of correlation, which measures the degree of association or mutual dependence of the two variables included in such double entry tables. This coefficient measures the amount of resemblance or association be- tween characteristics of individuals or things. It is stated in the form of a decimal which may take any value between 0 and 1. As the correlation coefficient rises to 1 we approach a condition of absolute dependence of the variables one upon the other. As it falls to zero we approach a condition of absolute independence, where the one variable has no relation to the other in the amount THE INHERITANCE OF DURATION 169 or direction of its variation. The significance of a cor- relation coefficient is always to be judged, in any partic- ular case, by the magnitude of a constant associated with it called the probable error. A correlation coeffi- cient may be regarded as certainly significant when it has a value of 4 or more times that of its probable error, which is always stated after the coefficient with a com- bined plus and minus sign between the two. The coeffi- cient is probably significant when it has a value of not less than 3 times its probable error. By ‘‘significant’’ in this connection is meant that the coefficient probably is not merely a random chance result. In Table 18 are the numerical results from the first study based upon the ‘‘Peerage’’ and ‘‘ Landed Gentry.’’ TABLE 18 Inheritance of duration of life in male line. Data from “Peerage’’ and “Landed Gentry.” (Beeton and Pearson). Ratio of Relatives Correlation | coefficient to coefficient | its probable error z y Toy Meat E, Father (‘‘Peerage’’) Son, 25 years and over | .115 + .021 5.5 Father (“Landed Gentry”) | Son, 20 years and over| .142+.021] 6.8 Father (“Peerage”) Son, 52.5 years and over | .116 + .023 5.0 Father (“Landed Gentry”) | Son, 50 years and over | .113 + .024 4.7 Brother (“Peerage’’) Brother .260 + .020 13.0 It is seen at once that all of the coefficients are signifi- cant in comparison with their probable errors. The last column of the table gives the ratio of the coefficient to its probable error, and in the worst case the coefficient is 4.7 times its probable error. The odds against such a correlation having arisen from chance alone are about 655 to 1. Odds such as these may be certainly taken as demonstrating that the results rep- 170 BIOLOGY OF DEATH resent true organic relationship and not mere chance. All of the other coefficients are certainly significant, hav- ing regard to their probable errors. Furthermore, they are all positive in sign, which implies that a variation in the direction of increased duration of life in one relative of the pair is associated with an increase in expectation of life in the other. It will be noted that the magnitude of the correlation between brother and brother is about twice as great as in the case of correlation of father with son. From this it is provisionally concluded that the " intensity of the hereditary influence in respect of duration of life is greater in the fraternal relationship than in the parental. It evidently makes no difference, broadly speaking, so far as these two sets of material are con- cerned, whether there are included in the correlation table all adult sons, whatever their age, or only adult sons over 50 years of age. The coefficients in both cases are es- sentially of the same order of magnitude. Perhaps someone will be inclined to believe that the correlation between father and son, and brother and brother, in respect of the duration of life arises as a result of similarity of the environments to which they are exposed. Pearson’s comments on this point are penetrating, and I believe absolutely sound. He says: There may be some readers who will be inclined to consider that much of the correlation of duration of life between brothers is due to there being a likeness of their environment, and that thus each pair of brethren is linked together and differentiated from the general population. But it is difficult to believe that this really affects adult brothers or a father and his adult offspring. A man who dies between 40 and 80 can hardly be said to have an environment more like that of his brother or father, who died also at some such age. than like any other member of the general popula- tion. Of course, two brothers have usually a like environment in infancy, and their ages at death, even if they die adults, may be influenced by their rearing. But if this be true, we ought to find a high correlation in ages THE INHERITANCE OF DURATION 171 at death of brethren who die as minors. As a matter of fact this correla- tion for minor and minor is 40 to 50 per cent. less than in the case of adult and adult. It would thus seem that identity of environment is not the principal factor in the correlation between ages of death, for this correlation is far less in youth than in old age. TABLE 19 Inheritance of duration of life. Data from Quaker records. (Beeton and Pearson) Relatives Correlation eet as ite coefficient probable error z y Ty Tay E, Father Adult son 0.1385 + .021 6.4 Father Minor son .087 + .022 4.0 Father Adult daughter . 130 + .020 6.5 Father Minor daughter -052 + .023 2.3 Mother Adult son .181 + .019 6.9 Mother Minor son .076 + .024 3.2 Mother Adult daughter -149 + .020 7.5 Mother Minor daughter -188 + .024 5.7 Elder adult brother | Younger adult brother | .229 + .019 12.1 Adult brother Adult brother .285 + .020 14.3 Minor brother Minor brother -103 + .029 3.6 Adult brother Minor brother ~.026 + .025 1.0 Elder adult sister Younger adult sister . .346 + .018 19.2 Adult sister Adult sister .332 + .019 17.5 Minor sister Minor sister .175 + .031 5.6 Adult sister Minor sister —.026 + .029 9 Adult brother Adult sister -232 + .015 15.5 Minor brother Minor sister .144 + .025 5.8 Adult brother Minor sister —.006 + .035 2 Adult sister Minor brother —.027 + .024 1.1 The cases above the horizontal line are all direct lineal inheritance; those below the line collateral inheritance. The results regarding minors to which Pearson refers are shown in Table 19. This table gives the results of the second study made by Beeton and Pearson on inher- itance of duration of life, based upon the records of the 172 BIOLOGY OF DEATH Friends’ Societies. It appears in the upper half of the table that wherever a parent, father or mother, appears with a minor son or daughter the correlation coefficients are small in magnitude. In some cases they are just barely significant in comparison with their probable errors as for example, the correlation of father and minor son, and that of mother and minor daughter. In the other cases involving minors the coefficients are so small as to be insignificant. On the other hand, in every case of correlation between parent and adult offspring of either sex, the coefficient is 6 or more times its probable error, and must certainly be regarded as significant. It will further be noted that the magnitude of the coefficients obtained from these Quaker recordsis of the same general order as was seen in the previous table based on the ‘“‘Peerage’’ and ‘‘Landed Gentry’’ material. The lower part of the table gives the results for various fraternal relationships. In general the frater- nal correlations are higher that the parental. The coeffi- cients for minors or for minors with adults are very low and in most cases not significantly different from zero. In four cases—namely, adult brother with minor brother; adult sister with minor sister; adult brother with minor sister; and adult sister with minor brother—the coeffi- cients are all negative in sign, although in no one of the cases is the coefficient significant in comparison with its probable error. A minus sign before a correlation coefficient means that an increase in the value of one of the variables is associated with a decrease in the value of the other. So that these negative coefficients would mean, if they were significant, that the greater the age at death of an adult brother, the lower the age at death of his minor brother or sister. But the coefficients are actually sensibly equal to zero. Pearson THE INHERITANCE OF DURATION 173 points out that the minus sign in the case of these correla- tions of adult with minor exhibits the effect of the inheri- tance of the mortality of youth. Minors dying from 16 to 20 are associated with adults dying from 21 to 25. That is, minors dying late correspond to adults dying early. This situation may be a peculiarity of the Quaker material with which this work deals. There is urgent need for further study of the inheritance of the duration of life on more and better material than any which has hitherto been used for the purpose. I have under way in my own laboratory at the present time an extensive investigation of this kind, in which there will be hundreds of thousands of pairs of relatives in the individual correlation tables instead of thousands, and all types of collateral kinship will be represented. Because of the magnitude of the investigation, however, it will be still a number of years before the results will be in hand for discussion. The facts which have been presented leave no doubt as to the reality of the inheritance factor as a prime determinant of the length of the life span. At the beginning it was pointed out that it was on a priors grounds highly probable that duration of life is influenced by both heredity and environment, and that the real problem is to measure the comparative effect of these two general sets of factors. We have seen that the intensity of inheritance of duration of life, taking aver- ages, is of the order indicated by the following coefficients. Parental correlation (adult children) r= .1365 Fraternal correlation (adults) r= 28381 Now we have to ask this question: What are the values of parental and fraternal correlation for characters but slightly if at all affected in their values by the environ- ment? Happily, Pearson has provided such values in his 174 BIOLOGY OF DEATH extensive investigations on the inheritance of physical characters in man. In Table 20 are given the values of the parental correlations for the four physical characters—stature, span, forearm length, and eye color. Now it is obvious TABLE 20 Parental inheritance of physical characters in man. (Pearson) Pair Organ Correlation Father and Son.................. Stature .............. 51 Father and Son.................. SPR wicca ewnrneames?. . 45 Father and Son.................. Forearm ...........-- 42 Father and Son.................. Eye color............. .55 Father and Daughter ............ Stature .............. 1 Father and Daughter ............ SPAN acesevan esses os 45 Father and Daughter ............ Forearm ............. 42 Father and Daughter ............ Eye color............. 44 Mother and Son................. Stature .............. .49 Mother and Son................. SPA ws. cevacwe sens .46 Mother and Son................. Forearm ............. 41 Mother and Son................. Eye color............. 48 Mother and Daughter............ Stature .............. 51 Mother and Daughter............ Span v3 osisetawo veces 45 Mother and Daughter............ Forearm ............. -42 Mother and Daughter............ Eye color............. 51 that the differences of environmental forces impinging upon the various members of a homogeneous group of middle class English families (from which source the . data for these correlations were drawn) can by no pos- sibility be great enough to affect sensibly the stature, the arm-length, or the eye color of the adults of such families. It would be preposterous to assert that the resemblance between parents and offspring in respect of eye color is due solely, or even sensibly, to similarity of environment. It is due to heredity and substantially nothing else. Now the average value of the 16 parental coefficients for the inheritance of physical characters shown in the table is r= .4675 THE INHERITANCE OF DURATION 175 _ Table 21 shows the coefficients for the fraternal in- heritance of six physical characters, cephalic index (the ratio of head length and head breadth) and hair color having been added to those given in the parental table. Again it is seen that the coefficients have all about the TABLE 21 Fraternal inheritance of physical characters in man. (Pearson) Pair Organ Correlation Brother and Brother............. Stature ssos0 545s ssas x 61 Brother and Brother............. SPER cdea ee aieeets .55 Brother and Brother ............. Forearm.............. .49 Brother and Brother ............. Eye color............. 52 Brother and Brother............. Cephalic index........ 49 Brother and Brother............. Hair color............ .59 Sister and Sister ................. Stature.............06 54 Sister and Sister ................. SPAN. ccsssisces Y asiee 56 Sister and Sister ................. Forearm............6+ 61 Sister and Sister ................. Eye color............. 45 Sister and Sister ................. Cephalic index........ 54 Sister and Sister ................. Hair color ............ .56 Brother and Sister ............... Stature.............05 55 Brother and Sister ............... SPAlesschadads taaaws 53 Brother and Sister ............... Forearm..........+0. 44 Brother and Sister ............... ‘Eye color............. 46 Brother and Sister............... Cephalic index........ 48 Brother and Sister ............... Hair color ............ .56 same values, and it is as apparent as before that the resemblance between brother and sister, for example, in eye-color, or arm length, or shape of head cannot for a moment, because of the nature of the characters them- selves, be supposed to have arisen because of the simi- larity of environment. The average value of all these fraternal coefficients is r= .5156 From these data, with the help of a method due to Pearson, it is possible to determine the percentage of the 176 BIOLOGY OF DEATH death rate dependent upon the inherited constitution, and the percentage not so dependent. If »N be the number of deaths in N cases which depend in no way upon the inherited constitution of the individual, then (1-p) will represent the chance of an individual dying because of his inherited constitutional makeup, and (1-p)? will be the chance of a pair of individuals, say two brothers, both dying from causes determined by inheritance. If further r denotes the observed correlation between individuals in respect of duration of life, and r, the correlation between the same kin in respect of such measured physical charac- ters as those just discussed, in the determination of which it is agreed that environment can play only a small part, we have the following relation: Tr Fe MEP)? Substituting the ascertained values we have 1. From parental correlations. 0.1365 = .4675 (1-p)? (1-p) 2 = .292 (1-p) = .54 2. From fraternal correlations 0.2831 = .5156 (1-p)? (1-p) = .74 From these figures it may be concluded, and Pearson does so conclude, that from 50 to 75 per cent. of the general death rate within the group of the population on which the calculations are based, is determined funda- mentally by factors of heredity and is not capable of essential modification or amelioration by any sort of environmental action, however well intentioned, however costly, or however well advertised. Mutatis mutandis the same conclusion applies to the duration of life. I have THE INHERITANCE OF DURATION 177 preferred to state the conclusion in terms of death rates, as it was originally stated by Pearson, because of the bearing it has upon a great deal of the public health propaganda so loosely flung about. It need only be re- membered that there is a perfectly definite functional relation between death rate and average duration of life in an approximately stable population group, expres- sible by an equation, in order to see that any conclusion as to the relative influence of heredity and environment upon the general death rate must apply with equal force to the duration of life. THE SELECTIVE DEATH RATE IN MAN If the duration of life were inherited it would logical- ly be expected that some portion of the death rate must be selective in character. For inheritance of duration of life can only mean that when a person dies is in part determined by that individual’s biological constitution or makeup. And equally it is obvious that individuals of weak and unsound constitution must, on the average, die earlier than those of strong, sound, and vigorous con- stitution. Whence it follows that the chances of leaving offspring will be greater for those of sound constitution than for the weaklings. The mathematical discussion which has just been given indicates that from one-half to three-fourths of the death rate is selective in char- acter, because that proportion is determined by hereditary factors. Just in proportion as heredity determines the death rate, so is the mortality selective. The reality of the fact of a selective death rate in man can be easily shown graphically. In Figure 44 are seen the graphs of some data from European royal families, where no neglect of children, 12 178 BIOLOGY OF DEATH degrading environmental conditions, or economic want can have influenced the results. These data were com- 50 r-— 45 }— % = = oS ee he Q 30 S = o 2 - b 2 >— . Ra 20 /— ao gs ———— MOTHER Ano CHILDREN x a eee FATHER ano CHILDREN = S jo 5. bene 0 Pesce Le NY ps le 6 2 GG 46 S56 66 76 86 and over AGE AT DEATH OF PARENTS Fie. 44.—Diagram showing the influence of age at death of parents upon the percentage of offspring dying under 5 years. (After Ploetz). piled by the well-known German eugenist, Professor Ploetz of Munich. The lines show the falling per- THE INHERITANCE OF DURATION 179 centage of the infantile death rate as the duration of life of the father and mother increases. Among the chil- dren of short-lived fathers and mothers, at the left end of each line, is found the highest infant mortality, while among the offspring of long-lived parents the lowest infant mortality occurs, as shown at the right-hand end of the diagram. The results so far presented regarding a selective death rate and inheritance of duration of life, have come from selected classes: the aristocracy, royalty or Quakers. None of these classes can be fairly said to represent the general population. Can the conclusion be transferred safely from the classes to the masses? To the determina- tion of this point one of Pearson’s students, Dr. E. C. Snow, addressed himself. The method which he used was, from the necessities of the case, a much more complicated and indirect one than that of Pearson and Ploetz. Its essen- tial idea was to see whether infant deaths weeded out the unfit and left as survivors the stronger and more resis- tant. All the infants born in a single year were taken as a cohort and the deaths occurring in this cohort in suc- cessive years were followed through. Resort was had to the method of partial or net correlation. The variables correlated in the case of the Prussian data were these: 1. a == Births in year a given cohort started. 2. a, = Deaths in the first two years of life. 3. w, = Deaths in the next eight years of life. 4. a, = Deaths in the ten years of all individuals not included in the particular cohort whose deaths are being followed. In the case of the English data the variables were: w, = Births in specified year. aw, = Deaths in the first three years of life of those born in specified year. w#, = Deaths in fourth and fifth years of life of those born in ' specified year. w, = The “remaining” deaths under 5. ¢ 180 BIOLOGY OF DEATH The underlying idea was to get the partial or net correlation between x, and 2, while x, and x, are held constant. If the mortality of infancy is selective, its amount should be negatively correlated to a significant degree with the mortality of the next eight years when the births in each district considered are made con- stant and when the general health environment is made constant. Under the constant conditions specified a negative correlation denotes that the heavier the infan- TABLE 22 Snow’s results on selective death rate in man. English and Prussian rural districts Actual correlation ‘ d t Data a || ee Males: English Rural (1870) -0.4483 —0.0828 Districts (1871) — .3574 - .1014 (1872) — ,2271 — .0807 Prussian Rural (1881) — .9278 — .0958 Districts (1882) — .6050 - .0765 Females: English Rural (1870) — .4666 - .0708 Districts (1871) — .2857 - .0505 (1872) — .5089 — .0496 Prussian Rural (1881) — .8483 - .0933 Districts (1882) —- .6078 - .0705 tile death rate in a cohort of births the lighter will be the death rate of later years, and vice versa. The last variable, 3, is the one chosen, after careful consideration and many trials, to measure variation in the health envi- ronment. If any year is a particularly unhealthy one—an epidemic year for example—then this unhealthiness should be accurately reflected in the deaths of those mem- bers of the population not included in the cohort under review. THE INHERITANCE OF DURATION 181 Snow’s results for English and Prussian rural dis- tricts are set forth in Table 22. From this table it is seen that in every case the correlations are negative, and therefore indicate that the mortality of early life is selec- tive. Furthermore, the demonstration of this fact is completed by showing that the observed coefficients are from 3 to 10 times as great as they would be if there were no selective character to the death rate. The coefficients for the Prussian population, it will be noted, are of a distinctly higher order of magnitude than those for the English population. This divergence is probably due chiefly to differences in the quality of the fundamental statistical material in the two cases. The Prussian ma- terial is free from certain defects inherent in the English data, which cannot be entirely got rid of. The difference in the coefficients for the two successive Prussian cohorts represents, in Snow’s opinion, probably a real fluctua- tion in the intensity of natural selection in the one group as compared with the other. How significant Snow’s results are is shown graphically in Figure 45. Snow’s own comments on his results are significant. He says: The investigations of this memoir have been long and laborious, and the difficulties presented by the data have been great. Still, the general result cannot be questioned. Natural selection, in the form of a selective death-rate, is strongly operative in man in the early years of life. Those data which we believe to be the best among those we have used—the Prus- sian figures—show very high negative correlation between the deaths in the first two years of life and those in the next eight, when allowance is made for difference in environment. We assert with great confidence that a high mortality in infancy (the first two years of life) is followed by a corresponding low mortality in childhood, and conversely. The English figures do not allow such a comprehensive survey to be undertaken, but, so far as they go, they point in the same direction as the Prussian. ones. The migratory tendencies in urban districts militate against the detection of selective influences there, but we express the belief that those influences 182 BIOLOGY OF DEATH are just as prevalent in industrial as in rural communities, and could be measured by other means if the data were forthcoming. 40 Veo SRR Soe 0, < MALES ay <% <> x x BS Ly Nes oon $26 $5 es SxS xo eee sock rates x SX xR 53 S35 << ves \7 so x ras Mes SS es res ener et ves Mes < res On, ne SxS ees ses Sx <3 55 Nes Mes ox <0 Warw, Sx KS Sx ves es ss es O < > oS x 8 SS Sx S00 oe, KOS Se xe oS Sx S05 > $32% SSK arate’ o < O08, OL SO % 5 aces nes SS <3 x 3S a5 aces ox% SS = SS ates SOS ace Nes M7 oS $8 XS ese Sx <4 . Ss <% < ie 2X Se SX % ‘ 8 SS rae < < of So res <3 S SS Nes ese SH > ee aa x ee SS sac ox $< ves res Mes So Nes $ Nes SS es , bottles are kept in electric incubators at a constant temperature of 25° C., the small bottles being packed for convenience in wire baskets. All have the same food material, both in quality and quantity, so that the envi- ronmental conditions surrounding these flies during their life may be regarded as substantially constant and uni- form for all. Figure 48 shows the survival frequency, or J. line of a life table, for six different lines of Drosophila, which have been bred in my laboratory. Each line represents STUDIES ON THE DURATION OF LIFE 193 the survival distribution of the offspring of a single brother and sister pair mated together. In forming a line a brother and sister are taken as the initial start because by so doing the amount of genetic variation pres- ent in the line at the beginning is reduced to the lowest possible minimum. It should be said that in all of the curves in Figure 48, both male and female offspring are lumped together. This is justifiable for illustrative pur- poses because of the small difference in the expectation of life at any age between the sexes. The line of descent, No. 55, figured at the top of the diagram, gives an I. line extraordinarily like that for man, with the exception of the omission of the sharp drop due to infantile mor- tality at the beginning of the curve. The extreme dura- tion of life in this line was 81 days, reached by a female fly. The J. line drops off very slowly until age 36 days. From that time on, the descent is more rapid until 72 days of age are reached when it slows up again. Lines 50, 60, and 58 show J, curves all descending more rapidly in the early part of the life cycle than that for line 55, although the maximum degree of longevity attained is about the same in all of the four first curves. The general shape of the J. curves changes however, as is clearly seen if we contrast line 55 with line 58. The former is concave to the base through nearly the whole of its course, whereas the J. curve for line 58 is convex to the base practically throughout its course. While, as is clear from the dia- gram, the maximum longevity attained is about the same for all of these upper four lines, it is equally obvious that the mean duration of life exhibited by the lines falls off as we go down the diagram. The same process, which is in operation between lines 55 and 58, is continued in an even more marked degree in lines 61 and 64. Here not only is the descent more rapid in the early part of the 13 194 BIOLOGY OF DEATH lz curve, but the maximum degree of longevity attained ig much smaller, amounting to about half of that attained in the other four lines. Both lines 61 and 64 tend to show in general a curve convex to the base, especially in the latter half of their course. Since each of these lines of descent continues to show through successive generations, for an indefinite time, the same types of mortality curves and approximately the same average durations of life, it may safely be con- cluded that there are well marked hereditary differences in different strains of the same species of Drosophila in respect of duration of life. Passing from the top to the bottom of the diagram the average expectation of life is reduced by about two-thirds in these representative curves. For purposes of experimentation, each one of these lines of descent becomes comparable to a chemical reagent. They have standard durations of life, each peculiar to its own line and determined by the hereditary constitution of the individual in respect of this charac- ter. We may, with entire justification, speak of the flies of line 64 as hereditarily short-lived, and those of line 55 as hereditarily long-lived. Having established so much, the next step in the analy- sis of the mode of inheritance of this character is ob- viously to perform a Mendelian experiment by crossing an hereditarily short-lived line with an hereditarily long- lived line, and follow through in the progeny of succes- sive generations the duration of life. If the character follows the ordinary course of Mendelian inheritance, we should expect to get in the second offspring generation a segregation of different types of flies in respect of their duration of life. Figure 49 shows the result of such Mendelian experi- % STUDIES ON THE DURATION OF LIFE 195 ment performed on a large scale. In the second line from the top of the diagram, labeled ‘‘Type I I.,’’ we see the mortality curve for an hereditarily long-lived pure strain of individuals. At the bottom of the diagram the ‘‘Type IV Iz’? line gives the mortality curve for one of our heredita- rily short-lived strains. Individuals of TypeI andTypeIV (000 plane 900 T \ w=] Sa ~~ ~ as gay V1} KBB. Va NaS N, SERENE \ 4 \ \ aad N, ah ra \h “eh, \ 3 500 aN aN 5 NN 4 400 \ AN pe \ e a \A \ KW NK \ 200 \ oy AN KN A NS ‘ . 100 ‘ 2 AN Si ~. > o [7 6 az «8 a4 30 = 7. az “= 46 54 60 66 Te 3 64 90 AGE IN DAYS Fra, 49.—Life lines showing the result of Mendelian experiments on the duration of life in Drosophila. Explanation in text. were mated together. The result in the first offspring hybrid generation is shown by the line at the top of dia- gram marked ‘‘F,1,.’? TheF', denotes that this is the mor- tality curve of the first filial generation from the cross. It is at once obvious that these first generation hybrids have a greater expectation of life at practically all ages than do either of the parent strains mated together to produce the hybrids. The result is exactly comparable to that which has for some time been known to occur in plants, from the researches particularly of Kast and others with maize. Hast and his students have worked 196 BIOLOGY OF DEATH out very thoroughly the cause of this increased vigor of the first hybrid generation and show that it is directly due to the mingling of different germ plasms. The average duration of life of the Type I original parent stock is 44.2 + 4 days. The average duration of life of the short-lived Type IV flies is 14.1 + .2 days, or only about one third as great as that of the other stock. The average duration of life of the first hybrid genera- tion shown in the F, J, line is 51.54 .5 days. So that there is an increase in average duration of life in the first hybrid generation, over that of the long-lived parent, of approximately 7 days. In estimating the significance of this, one should remember that a day in the life of a fly corresponds, as has already been pointed out, almost exactly to a year in the life of a man. When individuals of the first hybrid generation are mated together to get the second, or F, hybrid generation we get a group of flies which, if taken all together, give the mortality curve shown in the line at about the middle of the diagram, labelled ‘‘All F, J-.’’ It, however, tells us little about the mode of inheritance of the character if we consider all the individuals of the second hybrid generation together, because really there are several kinds of flies present in this second hybrid generation. © There are sharply separated groups of long-lived flies and of short-lived flies. These have been lumped together to give the ‘‘All F,1,’’ line. If we consider separately the long-lived second generation group and the short-lived second generation group we get the results shown in the two lines labelled ‘‘Long-lived F, Segregates /:,’’ and “‘Short-lived F, Segregates /,.’’ It will be noted that the long-lived F’, segregates have a mortality curve which al- mostexactly coincides with that of the original parent Type I stock. In other words, in the second generation after STUDIES ON THE DURATION OF LIFE 197 the cross of the long-lived and short-lived types, a group of animals appears having almost identically the same form of mortality curve as that of one of the original parents in the cross. The mean duration of life of this long-lived second generation group is 43.3+ .4 days, while that of the original long-lived stock was 44.2 + 4 days. The short-lived F, segregates, shown at the bottom of the diagram, give a mortality curve essentially like that of the original short-lived parent strain. The two curves wind in and about each other, the F, flies showing a more rapid descent in the first half of the curve and a slower descent in the latter half. In general, however, the two are very clearly of the same form. The aver- age duration of life of these short-lived second generation segregates is 14.64 .6 days. This, it will be recalled, is almost identically the same average duration of life as the original parent Type IV gave, which was 14.1 + .2 days. It may occur to one to wonder how it is possible to pick out the long-lived and short-lived segregates in the second generation. This is done by virtue of the corre- lation of the duration of life of these flies with certain external bodily characters, particularly the form of the wings, so that this arrangement of the material can be made with perfect ease and certainty. These results show in a clear manner that duration of life, in Drosophila at least, is inherited essentially in accordance with Mendelian laws, thus fitting in with a wide range of other physical characters of the animal which have been thoroughly studied particularly by Morgan and his students. Such results as these just shown constitute the best kind of proof of the essential point which we are examining—namely, the fact that 198 BIOLOGY, OF DEATH duration of life is a normally inherited character. I do not wish at this time to go into any discussion of the details of the Mendelian mechanism for this character, in the first place, because it is too complicated and tech- nical a matter for discussion here* and, in the second place, because the investigations are far from being com- pleted yet. I wish here and now merely to present the demonstration of the broad general fact that duration of life is inherited in a normal Mendelian manner in these fly populations. The first evidence that this was the case came from some work of Dr. R. R. Hyde with Drosophila some years ago. The numbers involved in his experiment, however, were much smaller than those of the present experiments, and the preliminary demon- stration of the existence of pure strains relative to dura- tion of life in Drosophila was not undertaken by -him. Hyde’s results and those here presented are entirely in accord. With the evidence which has now been presented re- garding the inheritance of life in man and in Drosophila we may let that phase of the subject rest. The evidence is conclusive of the broad fact, beyond any question I think, coming as it does from such widely different types of life, and arrived at by such totally different methods as the statistical, on the one hand, and the experimental, on the other. We may safely conclude that the primary agent concerned in the winding up of the vital clock, and by the winding determining primarily and fundamentally how long it shall run, is heredity. The best insurance of longevity is beyond question a careful selection of one’s parents and grandparents. * Full technical details and all the numerical data regarding these and other Drosophila experiments referred to in this book will shortly be published elsewhere. STUDIES ON THE DURATION OF LIFE 199 BACTERIA AND DURATION OF LIFE IN DROSOPHILA But clocks may be stopped in other ways than by running down. It will be worth while to consider with some care a considerable mass of most interesting, and in some respects even startling, experimental data, re- garding various ways in which longevity may be influenced by external agents. Since we have just been considering Drosophila it may be well to consider the experimental evidence regarding that form first. It is an obviously well-known fact that bacteria are responsible in all higher organisms for much organ breakdown and consequent death. An infection of some particular organ or organ system occurs, and the disturbance of the balance of the whole so brought about finally results in death. But is it not possible that we overrate the importance of bacter- ial invasion in determining, in general and in the broad- est sense, the average duration of life? May it not be that when an organ system breaks down under stress of bacterial toxins, it is in part at least, perhaps primarily, because for internal organic reasons the resis- tance of that organ system to bacterial invasion has nor- mally and naturally reached such a low point that its defenses are no longer adequate? All higher animals live constantly in an environment far from sterile. Our mouths and throats harbor pneumonia germs much of the time, but we do not all or always have pneumonia. Again it may fairly be estimated that of all persons who attain the age of 35, probably at least 95 per cent. have at some time or other been infected with the tubercle bacillus, yet fewer than one in ten break down with active tuberculosis. What plainly is needed in order to arrive at a just estimate of the relative influence of bacteria and their 200 BIOLOGY OF DEATH toxins in determining the average duration of life is an experimental inquiry into the effect of a bacteria-free, sterile mode of life. Metchnikoff has sturdily advocated the view that death in general is a result of bacterial intoxication. Now a bacteria-free existence is not pos- sible for man. But it is possible for certain insects, as was first demonstrated by Bogdanow, and later con- firmed by Delcourt and Guyenot. If one carefully washes either the egg or the pupa of Drosophila for 10 minutes in a strong antiseptic solution, say 85 per cent. alcohol, he will kill any germ which may be upon the surface. If the bacteria-free egg or pupa is then put into a sterile receptacle, containing only sterile food material and a pure culture of yeast, development will occur and pre- sently an adult imago will emerge. Adult flies raised in this way are sterile. They have no bacteria inside or out. Normal healthy protoplasm is normally sterile, so what is inside the fly is bound to be sterile on that account, and by the use of the antiseptic solution what bacteria were on the outside have been killed. The problem now is, how long on the average do such sterile specimens of Drosophila live in comparison with the ordinary fly, which is throughout its adult life as much beset by bacteria relatively as is man himself, it . being premised that in both cases an abundance of prop- er food is furnished and that in general the environ- mental conditions, other than bacterial, are made the same for the two sets? Fortunately, there are some data to throw light upon this question from the experiments of Loeb and his associate Northrop on the duration of life in this form, taken in connection with experiments in the writer’s laboratory. Loeb and Northrop show that a sample of 70 flies, of the Drosophila with which they worked, which were STUDIES ON THE DURATION OF LIFE 201 proved by the most careful and critical of tests to have remained entirely free of bacterial contamination through- out their lives, exhibited, when grown at a constant tem- perature of 25° C. an average duration of life of 28.5 days. In our experiments 2,620 male flies, of all strains of Drosophila in our cultures taken together, thus giv- ing a fair random sample of genetically the whole Droso- phila population, gave an average duration of life at the same constant temperature of 25° C. of 31.3 +.3 days, and 3,216 females under the same temperature lived an average of 33.0 +.2 days These were all non-sterile flies, subject to all the bacterial contamination incident to their normal laboratory environment, which we have seen to be a decaying germ-laden mass of banana pulp and agar. It is thought to be fairer to compare a sample of a general population with the Loeb and Northrop figures rather than a pure strain because probably their Droso- phila material was far from homozygous in respect of the genes for duration of life. The detailed comparisons are shown in Table 23. TABLE 23 Average duration of life of Drosophila in the imago stage at 26° C. : Mean duration Number of Experimental group of life in days ies Sterile (Loeb and Northrop) ................. 28.5 70 Non-sterile, males, all genetic lines (Pearl) 31.3 2620 Non-sterile, females, all genetic lines (Pearl) 33.0 3216 Non-sterile, both sexes, all genetic lines (Pear!) 32.2 5836 Difference in favor of non-sterile ............. 3.7 Probable error of difference about ............ + 1.0 We reach the conclusion that bacteria-free Drosophila live no longer on the average, and indeed perhaps even a little less long, under otherwise the same constant 202 BIOLOGY OF DEATH environmental conditions, than do normal non-sterile— indeed germ-laden—flies. This result is of great inter- est and significance. It emphasizes in a direct experi- mental manner that in a broad biological sense bacteria play but an essentially accidental réle in determining length of the span of life in comparison with the influence of heredity. POVERTY AND DURATION OF LIFE But we must take care lest we seem to convey the impression that no sort of environmental influence can affect the average duration of life. Such a conclusion would be manifestly absurd. Common sense tells us PERSONAL PROPERTY TAX IN PARIS IDI- 1913 CD payine GB xem 100 -- 90 sol 2 aed eg 2 sok & 40 b RK 3goF a | Ob o 716 02354245 BN 81920 1 f @ MW PRS CLASSES OF ‘ARRONDISSEMENT ARRONDISSEMENTS Fig. 50.—Distribution of poverty in Paris (1911-13) as indicated by exemption from personal property tax. (After Hersch). that environmental conditions in general can, and under some circumstances, do exert a marked influence upon expectation of life. A recent study of great interest and suggestiveness, if perhaps some lack of critical sound- ness, by the eminent Swiss statistician, Hersch, may be cited in this connection. Hersch became interested in the relation of poverty to mortality. He gathered STUDIES ON THE DURATION OF LIFE 203 data from the 20 arrondissements of the city of Paris in respect of the following points, among others: a. Percentage of families not paying a personal property tax. b. Death rate per 1000 from all causes. ce. Stillbirths per 1000 living births. Figure 50 shows in the black the percentage of fam- ilies too poor to have any personal property tax assessed, first for each arrondissement separately, then at the MORTALITY IN PARIS = IDI - 1913 = 2 ee , Se eb S35 tw % Se ob z 8 ost O68 6 176 2OSBRASUEH 92B 10 a0 YW Paris CLASSES OF ARRONDISSEMENTS “ARRONDISSEMENTS Fig. 51.—Death rates in Paris (1911-13) from all causes. (After Hersch). right in broader bars for the four groups of arrondisse- ments separated by wider spaces in the detailed dia- gram, and finally for Paris as a whole. It will be seen that the poverty of the population, measured by the per- sonal property yardstick, is least at the left-hand end of the diagram, where the smallest percentages of fam- ilies are exempted from the tax, and greatest at the right-hand end, where scarcely any of the population is well enough to do to pay this tax. , Figure 51 shows the death rates from all causes for the same arrondissements and the same groups. It is at once apparent that the black bars in this group run in a general manner parallel to the preceding one. The 204 BIOLOGY OF DEATH poorest districts have the highest death rates, the richest districts the lowest death rates, and districts interme- diate in respect of poverty are also intermediate in res- pect of mortality. On the face of the evidence there would seem to be here complete proof of the overwhelm- ingly important influence upon duration of life of degree of poverty, which is perhaps the most potent single envi- ronmental factor affecting civilized man to-day. But, alas, pitfalls proverbially lurk in statistics. Before we can accept this so alluring result and go along with our author to his final somewhat stupendous conclusion that if there were no poverty the death rate from certain im- portant causes, as for example tuberculosis, would forth- with become zero, we must exercise a little inquisitive caution. What evidence is there that the inhabitants of the districts showing a high poverty rate are not biologi- cally as well as economically differentiated from the in- habitants of districts with a low poverty rate? And again what is the evidence that it is not such biological differentiation rather than the economic which determines the death rate differences in the two cases? Unfortunately, our author gives us no whit of evidence on these obviously so important points. He merely assumes, because of the facts shown, that if some omnipotent spook were to trans- pose all the inhabitants of the Menilmontant arrondisse- © ment to the Elysee arrondissement, and vice versa for example, and were to permit each group to annex the worldly goods of the dispossessed group, then the death rates would be forthwith interchanged. There is no real evidence that any such result would follow at all. One cannot shake in the slightest degree from its solidly grounded foundation the critically determined fact of the paramount importance of the hereditary factor in determining rates of mortality, which have been summa- STUDIES ON THE DURATION OF LIFE 205 rized in this and the preceding chapter by any such evi- dence as that of Hersch. TABLE 24 Stillbirths in Paris (1911-18) by classes of arrondissements (Hersch) Absolute figures Stillbirths Classes of Arrondissements per 100 living Stillbirths Living births births I 1,004 12,313 8.2 II 1,390 19,998 7.0 IIl 7,279 82,821 8.8 ‘ IV 3,024 30,853 9.8 Paris 12,679 145,985 8.7 This, indeed, he himself finds to be the fact when he considers the extremely sensitive index of hereditary biological constitution furnished by the stillbirth rate. Table 24 gives the data. We see at once that there is no such striking increase in the foetal mortality as we pass from the richest class of districts, as was shown in the death rate from all causes. Instead there is practically no change, certainly none of significance, as we pass from one class of districts to another. The rate is 8.2 per 100 living births in the richest class and 9.8 in the poorest. Other definite evidence that such conclusion as those of Hersch cannot be accepted at anything like their face value is afforded by the work of Greenwood and Brown on the relation of poverty and the infant death rate. They find, giving subscripts the following meanings: Subscript 1 = Birth rate Subscript 2 = Artificial feeding rate Subscript 3 = Poverty rate Subscript 4 = Infant death rate that 734.12 — A7+ .07 on the basis of the Bavarian data of Groth and Hahn. 206 BIOLOGY OF DEATH Now this is a statistically insignificant net correlation, being less even than 3 times its probable error. It means that, when the birth rate and artificial feeding rate are held constant, differences in the infant death rate are not sufficiently influenced or determined by differences in the poverty rate to lead to a coefficient of correlation significantly different from zero, so far as Bavarian populations are indicative. This result is further confirmed by an analysis which Greenwood and Brown made of Heron’s London mate- rial, showing that in that case 724.1 = 19 + .13 This coefficient means that the differences in infant mortality rate in the different districts of London, when the birth rate is made constant, are not associated with differences in poverty between the same districts to an extent sufficient to lead to a correlation coefficient sensi- bly different from zero. Finally, Stevenson has, since the appearance of Hersch’s paper, studied the same problems on the basis of the London data, for the sake of comparison with the results from Paris. He takes as the index of eco- nomic status the number of domestic servants (of both sexes) per 100 of population, and has examined the death’ rates from all causes, infant mortality, and tuberculosis for the identical years that Hersch used. The results are set forth in Table 24a. Commenting on the facts regarding general mortality from all causes in London, Stevenson says: “These bear an altogether different aspect from the Parisian figures. Whereas the latter increase so regularly with poverty that the highest rate for any district in one group never exceeds the lowest for any district in the next poorer group, in London the gradation, even for the groups themselves, is irregular, the lowest death-rate not being returned for the STUDIES ON THE DURATION OF LIFE 207 TABLE 248 Mortality of London boroughs grouped by wealth. (From Stevenson) 2nd Death-rate Infant mortality Death-rate 8 22 | from all causes, iiberoutcis beeline 1918-19 {1911-131 1911-13 QBs 1 Be 1 3 33 ® + a 4 @ _ CO) eo) FS aa 3 3 & #3 8 ao] Che) age) 6 | BF] 8] gk) 6 | 8 | 3 eo Q pia n Kensington ......... 16.67 | 18.7] 18.6] 83 | 221 | 112 | 1.32] 1.32 Hampstead ......... 16.40 | 10.4] 11.0] 64 | 236 72 | 0.81] 0.80 Westminster ........{15.17 | 12.6] 13.3] 77 | 235 94 | 1.49) 1.42 Chelsea... .........- 14.96 | 14.7] 14.0] 78 | 155 91 | 1.64] 1.61 Marylebone......... 12.98 | 14.3] 14.6] 79 | 250 98 | 1.70] 1.66 Paddington ......... 10.42} 13.3] 18.2] 88 | 237 | 109 | 1.33] 1.31 Group I......... 14.38 | 138.2] 18.4] 80 | 228 | 100 | 1.39] 1.36 Cite sh: bata aaa 6.46 | 14.0] 14.6} 122 | 278 97 | 1.95] 1.84 Lewisham........... 5.71] 11.38] 11.1] 51 | 294 84 | 1.09] 1.01 Wandsworth ........ 5.67 | 11.5] 11.6] 72 | 240 96 | 1.20} 1.18 Stoke Newington ....| 4.98 | 13.0] 12.4] 71 | 231 85 | 1.30] 1.28 Holborn............ 4.388] 15.1] 15.2] 99 | 267 | 102 | 2.30] 2.17 Greenwich.......... 4.10] 13.9] 13.7] 93 | 349 | 102 | 1.60) 1.59 Group II........ 5.34] 12.2{ 12.1] 73 | 272 94 | 1.32] 1.30 Fulham............. 3.52 | 138.6] 14.1] 85 | 222 | 105 | 1.73] 1.69 Hammersmith....... 8.30 | 14.5] 14.3] 91 | 207 | 114 | 1.62] 1.58 Lambeth............ 3.18 | 14.3] 14.0] 82 | 217 | 105 | 1.71] 1.68 St. Pancras ......... 3.12] 15.1) 15.1] 81 | 226 98 | 1.91] 1.85 Hackney..... ..| 2.95] 18.5} 18.6] 83 | 355 | 100 | 1.68] 1.67 Woolwich........... 2.81 | 12.6] 12.9] 88 | 220 84 | 1.67) 1.65 Camberwell......... 2.68 | 13.8) 13.6] 83 | 268 99 | 1.61] 1.60 Deptford ........... 2.64] 15.0] 14.8] 87 | 176 | 117 | 1.73] 1.70 Battersea........... 2.62 | 18.6] 18.7] 74 | 276 | 107 | 1.56] 1.53 Islington............ 2.48 | 14.9] 14.5] 88 | 258 | 107 | 1.69] 1.66 Group ITI....... 2.90} 14.1] 14.0] 84 | 243 | 103 | 1.70} 1.67 Stepney ............ é : 90 | 314 | 121 | 2.15] 2.12 Finsbury............ ‘ i i: 91 | 229 | 187 | 2.47] 2.45 Southwark.......... ‘ 3 : 101 | 225 | 122 | 2.23} 2.17 Poplar......... we|> dbs F a 92 | 216 | 125 | 1.88) 1.86 Bermondsey......... :8{ 105 | 360 | 183 | 2.85] 2.31 Shoreditch.......... ; : .5] 124 | 255 | 150 | 2.47] 2.46 Bethnal Green....... 0.77 | 16.4) 17.1] 101 | 263 | 123 | 2.21] 2.21 Group IV....... 1.13 | 17.1] 17.4] 99 | 260 | 128 | 2.21) 2.18 County of London...| 4.74 | 14.4] 14.4] 86 | 247 | 109 | 1.71] 1.68 208 BIOLOGY OF DEATH richest group. Indeed, the difference between the first three London groups is slight, significant excess only being apparent for the poorest group. And whereas the excess of mortality of the poorest over the richest group in Paris is 104 per cent., in London it is only 30 per cent.” He then examines the question as to whether the dis- crepancies may be due to differences in the method of con- struction of the two sets of mortality figures and concludes: “That the remarkable contrast in experience between the two cities cannot be explained, except possibly in a very minor degree, by any differences of method in compilation of the statistics compared.” Stevenson then goes on to the discussion of infant mortality and says: “The conclusion just arrived at applies still more to infant than to total mortality, for, in its case, the contrast between rich and poor quarters of Paris assumes dimensions which, in the light of London experience, seem quite fantastic.” Regarding mortality from tuberculosis the London experience again fails to agree with the Paris experience, and Hersch’s conclusions from the data of the latter city would be absurd if applied to the former. EXPERIMENTS ON TEMPERATURE AND DURATION OF LIFE Altogether it is plain that we need another kind of evidence than the simple unanalyzed parallelism which Hersch demonstrates between poverty and the general death rate if we are to get any deep understanding of the influence of environmental circumstances upon the dura- tion of life or the general death rate. We shall do well to turn again to the experimental method. About a dozen years ago Loeb, starting from the idea that chemical conditions in the organism are one of the main variables in this case, raised the question whether there was a definite coefficient for the duration of life and whether this temperature coefficient was of the order of magnitude of that of a chemical reaction. The first experiments were made on the unfertilized and fertilized eggs STUDIES ON THE DURATION OF LIFE 209 of the sea urchin and could only be carried out at the upper temperature limits of the organism, since at ordinary temperatures this organism lives for years. In the upper temperature region the temperature coefficient for the duration of life was very high, probably on account of the fact that, at this upper zone of temperature, death is determined by a change of the nature of a coagulation or some other destructive process. Moore, at the suggestion of Loeb, investigated the temperature coefficient for the duration of life for the hydranth of a tubularian at the upper temperature limit and found that it was of the same order of magnitude as that previously found for the sea urchin egg. In order to prove that there is a temperature coefficient for the duration of life throughout the whole scale of temperatures at which an organism can live, experiments were required on a form whose duration of life was short enough to measure the duration of life even at the lowest temperature. A suitable organism was found in Drosophila. This was grown under aseptic conditions, as already described. The general results are shown in Table 25. TABLE 25 Effect of temperature on duration of life of Drosophila. (After Loeb and Northrop) Duration (in days) of Temperature Life of Total duration Larval stage Pupal stage imago of me a egg °C 10 57 Pup die 120.5 177.5+2 15 17.8 13.7 92.4 123.9 20 7.77 6.33 40.2 54.3 25 5.82 4.23 28.5 38.5 27.5 (4.15) 3.20 ame eas 30 4.12 3.43 13.6 21.15 From this table it is seen that at the lowest tempera- ture the duration of life is longest, and at the highest tem- perature shortest. Cold slows up the rate of living for the fly. Heat hastens it. One gathers, from the account which Loeb and Northrop give of the work, that at low temperature the flies are sluggish and inactive in all 14 210 BIOLOGY OF DEATH three developmental stages and perhaps live a long time because they live slowly. At high temperatures, on the other hand, the fly is very active and lives its life through quickly at the pace that kills.’’ These results are exactly comparable to the effect of a regular increase of tempera- ture upon a chemical reaction. Indeed, Loeb and North- rop consider that their results prove that With a supply of proper and adequate food the duration of the larval stage is an unequivocal function of the temperature at which the larve are raised, and the temperature coefficient is of the order of magnitude of that of a chemical reaction, 7. e., about 2 or more for a difference of 10° C. It increases at the lower and is less at the higher temperatures. The duration of the pupal stage of the fly is also an unequivocal function of the tempera- ture and the temperature coefficient is for each temperature practically identical with that for the larval stage. The duration of life of the imago is, with proper food, also an unequivocal function of the temperature and the temperature coefficient for the duration of life is, within the normal temperature limits, approximately identical with that for the duration of life of the larva and pupa. How are these results to be reconciled with the pre- vious finding that heredity is a primary factor in the determination of duration of life of Drosophila? We have here, on first impression at least, an excellent exam- ple of what one always encounters in critical genetic investigations: the complementary relations of heredity and environment. In our experiments a general mixed population of Drosophila kept under constant environ- ment was shown to be separable by selection into a num- ber of very diverse strains in respect of duration of life. In Loeb and Northrop’s experiments, a general mixed population of Drosophila, but of presumably constant genetic constitution, at least approximately such, through- out the experiment, was shown to exhibit changes of duration of life with changing environments. It is the old familiar deadlock. Heredity constant plus changing STUDIES ON THE DURATION OF LIFE 211 environment equals diversity. Environment constant plus varying hereditary constitution also equals diversity. Can we penetrate no farther than this into the matter? I think in the present case we can. In Loeb and Northrop’s experiments, temperature and duration of life were not the only two things that varied. The different tempera- ture groups also differed from each other—because of the temperature differences, to be sure, but not less really— in respect of general metabolic activity, expressed in muscular movement and every other way. In the gene- tic experiments metabolic activity was substantially equal in all the hereditarily different lines. The idea suggests itself, both on @ priort grounds and also upon the basis of certain experimental data presently to be in part re- viewed, that possibly duration of life may be an implicit function of only the two variables a. Genetic constitution b. Rate of metabolic activity. The functional relations of metabolic activity with temperature, food, light and other environmental fac- tors are all well known. For present purposes we do not need to go into the question of their exact form. The essential point is that all these environmental factors stand in definite functional relations to rate of metabolic activity, and do not so stand in relation to genetic consti- tution. Genetic constitution is not a function of the environment, but is, for any individual, a constant, and only varies between individuals. This may be thought merely to be an involved way of saying what one knows a priori: namely, that duration of life, in general and in particular, depends only upon heredity and environment. So in one sense itis. But the essential point I would make here is that the manner 212 BIOLOGY OF DEATH in which the environmental forces (of sub-lethal inten- sity, of course) chiefly act in determining duration of life, appears to be by changing the rate of metabolism of the dividual. Furthermore one would suggest, on this view, that what heredity does in relation to duration of life is chiefly to determine, within fairly narrow limits, the total energy output which the individual can exhibit in tts life time. This limitation is directly brought about presumably through two general factors: viz, (a) the kind or quality of material of which this particular vital machine is built, and (b) the manner in which the parts are put together or assembled. Both of these factors are, of course, expressions of the extent and charaeter of the processes of organic evolution which have given rise to this particular species about which we may be talking in a particular instance. There is some direct experimental evidence, small in amount to be sure, but exact and pertinent, to the effect that the duration of life of an animal stands in inverse re- lation to the total amount of its metabolic activity, or put in other words, to the work, in the sense of theoretical mechanics, that it as a@ machine does during its life. Slonaker kept 4 albino rats in cages like the old fashioned revolving squirrel cages, with a properly calibrated odo- meter. attached to the axle, so that the total amount of running which they did in their whole lives could be recorded. The results were those shown in Table 26. It will be perceived that the amount of exercise taken by these rats was astonishingly large. For a rat to run 5,447 miles in the course of its life is indeed a re- markable performance. Now these 4 rats attained an average age at death of 29.5 months. But three control rats confined in stationary cages so that they could only STUDIES ON THE DURATION OF LIFE 213 move about to a limited degree, but otherwise under conditions, including temperature, identical with those in the revolving cages, attained an average age at death of 40.3 months. All were stated to have died of ‘‘old TABLE 26 Relation of longevity to muscular activity in rats (Slonaker) TOTAL NUMBER OF MILES RUN DURING LIFE Age jin months Rat No. 1 No. 4 No. 2 No. 3 at death Miles Miles Miles Miles ZO ih eae 1265 BG ica genware cand 1391 Oto hxaaa ae Roe 2098 BA sds ss cileatt. olay: 5447 age.’’ From this experiment it clearly appears that the greater the total work done, or total energy output, the shorter the duration of life, and vice versa. Or, put another way, if the total activity per unit of time is in- creased by some means other than increasing tempera- ture, the same results appear as if the increased activity is caused by increased temperature. It appears, in short, to be activity per se, and not the temperature per se that is of real significance. There is other evidence, for which space lacks here, pointing in the same direction. An entirely different, and extremely suggestive line of evidence in favor of the view here set forth, has been given by Professor Max Rubner, the distinguished Ger- man student of the energy relations of the living organ- ism. Studying a considerable range of animals, he has found that all transform nearly the same total amount of energy, per kilo of body weight, in the whole period from their birth to their natural death. The mean value of the constant Rubner finds to be 191,600 calories, the values for different species ranging between 141,090 and 214 BIOLOGY, OF DEATH 265,500 calories. Small animals, with an intensive meta- bolism live a relatively short time; large animals with more sluggish metabolism live a longer time. Rubner’s view is that a definite sum of living action (energy trans- formation) determines the physiological end of life. This is precisely the view suggested here except that it is here postulated that the definite sum, for individual or species, is fundamentally determined by heredity, working through the structural make-up. If we may be permitted to make a suggestion regard- ing the interpretation of Loeb and Northrop’s results in conjunction with our own on Drosophila, it would be to this effect. Any given genetically pure strain of Droso- phila is made up of individual machines, constructed to turn out, before breaking down, a definite limited amount of energy in the form of work, mechanical, chemical and other. This definitely limited total energy output is predetermined by the hereditary constitution of the indi- vidual which fixes the kind of physico-chemical machine that that individual is. But the rate per unit of time of the energy output may be influenced between wide limits by environmental circumstances in general and tempera- ture in particular, since increased temperature increases rate of metabolic chemical changes in about the same ratio, as demonstrated by a wealth of work on tempera- ture coefficients, as it increases other chemical changes. But if the rate of energy outputper unit of time is changed, the total time taken for the total output of a predeter- mined amount of energy, as work, must change in inverse proportion to the change of rate. So we should expect just precisely the results on duration of life that Loeb and Northrop got, and so far from these results being in contradiction to ours upon heredity, they may be looked STUDIES ON THE DURATION OF LIFE 215 upon as a necessary consequence of them. Loeb and Northrop’s final conclusion is: ‘‘The observations on the temperature coefficient for the duration of life suggest that this duration is determined by the production of a substance leading to old age and natural death, or by the destruction of a substance or substances, which normally prevent old age and natural death.’’ The view which I have here suggested, completely incorporates this view within itself, if we suppose that the total amount of hypo- thetical ‘‘substance or substances which normally prevent old age and natural death’’ was essentially determined by heredity. This view I take to be in no way necessarily or funda- mentally contradictory to that set forth in this work. Whatever the factor which determines specific longev- ity may be; whether a specific chemical substance, as Loeb and Northrop suggest, or more generally, as I have suggested, the kind of material, in the sense of its biologi- cal fitness, composing the multicellular body, and the nature of the organization (in detail) of that material to form the multicellular body; it seems to me that we have now a sufficient mass of critical evidence to say that it is proved that quantitatively the effective magni- tude of this specific longevity factor in each particular case is determined by heredity. This I take to be of greater importance than the precise nature of the specific longevity factor itself, about which we are, admittedly, entirely ignorant. I can see nothing in the available evi- dence which definitely makes Loeb’s suggestion inherently more probable than mine. It does, however, seem clear that, by definitely showing the significance of the heredity element in the problem, help has been rendered the prog- ress of future research in the field. 216 BIOLOGY OF DEATH It would seem, at first thought, that one should be able to test the theory here suggested, that rate of energy expenditure in the business of living is negatively corre- lated with the total duration of life, by an examination of the mortality rates for persons in different occupations as set forth, for example, in the well known paper of Bertillon. When one endeavors to make such a test, however, he is at once confronted with a series of diffi- culties which presently convince him that the project is virtually an impossible one, if he wishes critical results. In the first place, mean age at death will not do as a criterion, because of the great differences in the age dis- tributions of those engaged in different occupations. This point has lately been thoroughly discussed by Collis and Greenwood, in their book ‘‘The Health of the Indus- trial Worker.’’ Indeed, their whole treatment of the prob- lem of occupational mortality is by far the most sound and critical which the present writer has yet seen. One must deal with age and sex specific death rates, or mor- tality indices based upon them. In the second place, there are specific hazards, direct or indirect, in various occupations, quite apart from any question of energy expenditure involved in the case. These hazards will, obviously, tend to obscure any direct effects of the energy relations involved. In the third place, we have only the merest suggestion of quantitatively accurate knowledge as to the average energy output involved indifferent trades and occupations. On the last point, a beginning to collect information has been made by Waller and his co-workers. In a re- cent paper Waller and De Decker have given the mean calory output, per hour, per square meter of body surface for a small sample of workers inafew trades. But the re- STUDIES ON THE DURATION OF LIFE 217 sults are far too meager, and, statistically, too unrepre- sentative to warrant any attempt at generalization from the present point of view. As in so many other cases the experimental method is likely to shed far more critical light on this problem than is the purely statistical method dealing with human data. There are too many factors in the latter material that cannot be controlled. GONADS AND DURATION OF LIFE There is another and quite different line of experi- mental work on the duration of life which may be touched upon briefly. The daily press has lately had a great deal to say about rejuvenation, accomplished by means of various surgical procedures undertaken upon the primary sex organs, particularly in the male. This newspaper notoriety has especially centered about the work of Voronoff and Steinach. The only experiments which, at the present time, probably deserve serious consideration are those of Steinach. He has worked chiefly with white rats. His theory is that, by causing through appropriate operative procedure, an extensive regeneration, in a sen- ile animal about to die, of certain glandular elements of the testis, senility and natural death will for a time be postponed because of the internal secretion poured into the blood by the regenerated ‘‘puberty glands”’ as he calls them. The operation which he finds to be most effective is to ligate firmly the efferent duct of the testis, through which the sperm normally pass, close up to the testis itself, and before the coiled portion of the duct is reached. The result of this, according to Steinach’s account, is to bring about in highly senile animals a great enlargement of all the sex organs, a return of sexualactivity, previously 218 BIOLOGY OF DEATH lost through old age, and a general loss of senile bodily characteristics and a resumption of the conditions of full adult vigor in those respects, together with a consid- erable increase in the total duration of life. Space is lacking to go into the many details of Steinach’s work, much of which is indeed chiefly of inter- est only to the technical biologist, and from a wholly different standpoint than the present one. I should, however, like to present one example from his experi- ments. As control, a rat was taken, in the last degree senile. He was 26 months old when the experiment be- gan. He was obviously emaciated, had lost much of his hair, particularly on the back and hind quarters. He was weak, inactive and drowsy, as indicated by the fact that his eyes were closed, and were, one infers from Steinach, kept so much of the time. A litter brother of this animal had the efferent ducts of the testes ligated. This animal, we are told, was, at the time of the operation, in so much worse condition of senility than his brother, above described, that it was not thought worth while even to photograph him. His con- dition was considered hopeless. To the surprise of the operator, however, he came back, slowly but surely after the operation, and after three and a half months pre- sented a perfect picture of lusty young rathood. He was in full vigor of every sort, including sexual. He outlived his brother by 8 months, and himself lived 10 months after the operation, at which time he was, accord- ing to Steinach, practically moribund. This represents a presumptive lengthening of his expected span of life by roughly a quarter to a third. It ts to be remembered, however, that Slonaker’s rats to which nothing was done lived to an average age of 40 months. STUDIES ON THE DURATION OF LIFE 219 The presumption that Steinach’s experiments have really brought about a statistically significant lengthen- ing of life is large, and the basis of ascertained fact small. After a careful examination of Steinach’s bril- liant contribution, one is compelled to take the view that, however interesting the results may be from the stand- point of functional rejuvenation in the sexual sphere, the case is not proven that any really significant length- ening of the life span has occurred. In order to prove such a lengthening we must, first of all, have abundant and accurate quantitative data as to the normal variation of normal rats in respect of duration of life, and then show, having regard to the probable errors involved, that the mean duration of life after the operation has been signi- ficantly lengthened. This Steinach does not do: His paper is singularly bare of statistical data. We may well await adequate quantitative evidence before attempting any general interpretation of his results. Indeed, one may note in passing that the case does not seem entirely clear in respect of Steinach’s results in the purely sexual sphere. Thus Romeis has repeated the experiments, and finds, from comparative histologi- cal studies on the genital organs of rats, before and after Steinach’s operation, that there is no evidence of any increase in Leydig’s interstitial cells, and hence none of the so-called ‘‘interstitial or puberty gland.’? Romeis noted no increase in sexual desire among his rats after the operation. The hypertrophy of the seminal vesicles and prostate, described by Steinach following the opera- tion, was also seen by Romeis, but found, by the latter, to be merely the result of the stasis of the secretions nec- essarily consequent upon the operation, and not a true functional hypertrophy at all. 220 BIOLOGY OF DEATH THE PITUITARY GLAND AND DURATION OF LIFE Robertson has been engaged for a number of years past on an extensive series of experiments regarding the effect of various agents upon the growth of white mice. The experiments have been conducted with great care and attention to the proper husbandry of the animals. In consequence, the results have a high degree of trust- worthiness. In the course of these studies he found that the anterior lobe of the pituitary body, a small gland at the base of the brain, normally secretes into the blood- stream minute amounts of an active substance which has amarked effect upon the normal rate of growth. By chemi- cal means, Robertson was able to extract this active sub- stance from the gland in a fairly pure state, and gave to it the name tethelin. In later experiments, the effect of tethelin, given by the mouth with the food, was tried in a variety of ways. In a recent paper, Robertson and Ray have studied the effect of this material upon the duration of life of the white mouse with the results shown in Table 27. TABLE 27 Effect of tethelin on duration of life in days of white mice. (Robertson and Ray) Both MALES FEMALES sexes together Chance Chance |} Chance Class of |Average| Dev. Dev. |dev. was||Average |R Dev. | ‘Dev. |dev. was||dev. was animals |duration| from | —— |acciden-|/duration| from acciden- |] acci- of life |normal| P. Z. tal of life |normal} P. E. tal dental Normal) 767 |. accasfaes cceleccececll FL9 donscecfe.s a66 lesan wenden Tethelin| 866 | +99 |3.00 |1:22.25)| 800 | +81 | 2.25 | 1:6.75 |/1:150.2 From this table, it is apparent that the administration of tethelin with the food from birth to death prolonged STUDIES ON THE DURATION OF LIFE 221 life to a degree which, in the case of the males, may be regarded as probably significant statistically. In the case of the females, where the ratio of the deviation to its probable error (Dev. /P. E.) falls to 2.25 the case is very doubtful. The procedure by which the chance of - 1:150.2 that results in both sexes together were acciden- tal, was obtained is of doubtful validity. Putting males and females together from the original table, I find the following results. TABLE 28 Duration of life of white mice, both sexes taken together (From data of Robertson and Ray) No.of _ |No. of deaths! Age deaths of tethelin Group of normals fed (Both sexes) |(Both sexes) 200-299 3 o Tethelin fed: Mean age at death —839+20 300-399 2 2a Normal fed: Mean age at death =743+17 400-499 2 1 Difference = 96426 ieee 3 : Difference = 3.7 700-799 | 15 i PE. nice 800-899 10 10 900-999 10 6 1000-1099 6 9 1100-1199 1 64 39 One concludes from these figures that tethelin can be regarded as having lengthened the span of life to a de- gree which is just significant statistically. One would expect, from the variation of random sampling alone, to get as divergent results as these about 114 times in every 100 trials with samples of 64 and 39, respectively. In any event it is apparent that, making out the best case possible, the differences in average duration of life 222 BIOLOGY OF DEATH produced by administration of tethelin are of a wholly different and smaller order than those which have been shown, in the earlier portion of this chapter, to exist be- tween pure strains of Drosophila which are based upon hereditary differences. Putting together all the results which have been re- viewed in this and the preceding chapter, it appears to be clearly and firmly established that inheritance is the factor of prime importance in determining the normal, natural duration of life. In comparison with this factor, the influence of environmental forces (of sub-lethal im- mediate intensity of course) appears in general to be less marked. CHAPTER VIII NATURAL DEATH, PUBLIC HEALTH, AND THE POPULATION PROBLEM. SUMMARY OF RESULTS I have attempted to review some of the important biological and statistical contributions which have been made to the knowledge of natural death and the duration of life, and to synthesize these scattered results into a coherent unified whole. In the present chapter I shall endeavor to summarize, in the briefest way, the scattered facts which have been passed in review, and to follow a presentation of the general results to which they lead with some discussion of what we may reasonably regard the future as having in store for us, so far as may be judged from our present knowledge of the trend of events. What are the general results of our review of the gen- eral biology of death? In the first place, one perceives that natural death is a relatively new thing, which appeared first in evolution when differentiation of cells for partic- ular functions came into existence. Unicellular ani- mals are, and always have been, immortal. The cells of higher organisms, set apart for reproduction in the course of differentiation during evolution, are immortal. The only requisite conditions to make their potential im- mortality actual are physico-chemical in nature and are now fairly well understood, particularly as a result of the investigations of Loeb upon artificial parthenogenesis and related phenomena. The essential and important 223 224 BIOLOGY OF DEATH somatic cells of the body, however much differentiated, are also potentially immortal; but the conditions neces- sary for the actual realization of the potential immor- tality are, in the nature of the case, as has been shown by the brilliant researches of Leo Loeb, Harrison and Carrel on tissue culture, such as cannot be realized so long as these cells are actually in and a part of the higher metazoan body. The reason why this is so, and why in consequence death results in the metazoa, is that, in such organisms the specialization of structure and function necessarily makes the several parts of the body mutually dependent for their life upon each other. If one organ or group, for any accidental reason begins to function abnormally and finally breaks down, the balance of the whole is upset and death eventually follows. But the individual cells, themselves, could go on living indefinitely, if they were freed, as they are in cultures, of the neces- sity of depending upon the proper functioning of other cells for their food, oxygen, ete. So then we see emerging, as our first, general result, the fact that natural death is not a necessary or inevit- able consequence of life. It is not an attribute of the cell. It is a by-product of progressive evolution—the price we pay for differentiation and specialization of structure and function. This first result indicates logically, in any particu- lar organism such as man, the great importance of a quantitative analysis of the manner in which dif- ferent parts of the body break down and lead to death. Such an analysis, carefully worked through, demonstrates that this breaking down is not a haphazard process, but a highly orderly one resting upon a fundamental biolog- ical basis. The progress of the basic tissue elements NATURAL DEATH, PUBLIC HEALTH ~— 225 of the body along the evolutionary pathway appears to be an important factor in determining the time when the organ systems in which they are chiefly involved shall break down. Those organ systems that have evolved farthest away from original primitive conditions are the soundest and most resistant, and wear the longest under the strain of functioning. So then, the second large result is that it is the way potentially immortal cells are put together in mutually dependent organ sys- tems that immediately determines the time relations of the life span. But it was possible to penetrate more deeply into the problem than this by finding that the duration of life is an inherited ‘character of an individual, passed on from parent to offspring, just as is eye color or hair color, and with a relatively high degree of precision. This has been proved in a variety of ways, first directly for man (Pearson) and for a lower animal, Drosophila, (Hyde, Pearl) by measuring the degree of hereditary transmis- sion of duration of life, and indirectly by showing that the death rate was selective (Pearson, Snow, Bell, Ploetz) and had been, since nearly the beginning of recorded his- tory, at least. It is heredity which determines the way the organism is put together—the organization of the parts. And it is when parts break down and the organ- ization is upset that death comes. So the third large re- sult is that heredity is the primary and fundamental determiner of the length of the span of life. Finally, it is possible to say probably, though not as yet definitely because the necessary mass of experimen- tal evidence is still lacking, but will, I believe, be shortly provided, that environmental circumstances play their 15 226 BIOLOGY OF DEATH part in determining the duration of life largely, if not in principle entirely, by influencing the rate at which the vital patrimony is spent. If we live rapidly, like Loeb and Northrop’s Drosophila at the high temperatures, our lives may be more interesting, but they will not be so long. The fact appears to be, though reservation of final judgment is necessary till more returns are in, that heredity determines the amount of capital placed in the vital bank upon which we draw to continue life, and which when all used up spells death; while environment, using the term in the broadest sense to include habits of life as well as physical surroundings, determines the rate at which drafts are presented and cashed. The case seems in principle like what obtains in respect of the duration of life of a man-constructed machine. It is self-evident that if, of two automobiles of the same make leaving the factory together new at the same time, one is run at the rate of 1,000 miles per year and the other at the rate of 10,000 miles per year, the useful life of the former is bound to be much longer in time that that of the latter, accidents being excluded in both cases. Again, a very high priced car, well-built of the finest material, may have a shorter duration of life than the poorest and cheapest machine, provided the annual mileage output © of the former is many times that of the latter. The first three of these conclusions seem to be firmly grounded. The last rests, at present, upon a less secure footing. Because it does, it offers an extremely promis- ing field for both statistical and experimental research. We need a wide variety of investigations, like those of Loeb and Northrop, of Slonaker and of Rubner, on the experimental side. On the statistical side, well-conceived NATURAL DEATH, PUBLIC HEALTH ~ 227 and careful studies, by the most refined of modern meth- ods, upon occupational mortality seem likely to yield large returns. PUBLIC HEALTH ACTIVITIES Fortunately, it is possible to get some light on the environmental side from existing statistical data by con- sidering, in a broad general way, the results of public health activities. Any public health work, of course, deals, and can deal in the present state of public senti- ment and enlightenment, only with environmental matters. Attempts at social control of the germ-plasm—the innate inherited constitutional make-up—of a people, by eugenic legislation, have not been conspicuously successful. And there is a good deal of doubt, having regard to all factors necessarily involved, whether they have always been even well-conceived. As an animal breeder of some years’ experience, I have no doubt whatever that almost any breeder of average intelligence, if given omnipotent control over the activities of human beings, could, in a few generations, breed a race of men on the average con- siderably superior—by our present standards—to any race of men now existing in respect of many qualities or attributes. But, as a practical person, I am equally sure that nothing of the sort is going to be done by legislative action or any similar delegation of powers. Before any sensible person or society is going to entrust the control of its germ-plasm to politics or to science, there will be demanded that science know a great deal more than it now does about the vagaries of germ-plasms and how to control them. Another essential difficulty is one of stan- dards. Suppose it to be granted that our knowledge of 228 BIOLOGY OF DEATH genetics was sufficiently ample and profound to make it possible to make a racial germ-plasm exactly whatever one pleased; what individual or group of individuals could possibly be trusted to decide what it should be? Doubtless many persons of uplifting tendencies would promptly come forward prepared to undertake such a responsibility. But what of history? If it teaches us anything, it is that social, moral and political standards are not fixed and absolute, but vary, and vary radically in both space and time. And further, history teaches that a great many of the most valuable people, in the highest and best sense, whom the world has ever known, were so constituted physically, morally} or otherwise, as to make it certain that under a strict eugenic regime they never would have existed at all. One cannot but feel that man’s instinctive wariness about experimental interferences with his germ-plasm is in considerable degree, well-founded. But because of the altogether more impersonal na- ture of the case, most men individually and society in general are perfectly willing to let anybody do anything they like in the direction of modifying the environment in what is believed, or hoped to be, the direction of improve- ment, or trying to, quite regardless of whether science is able to give any slightest inkling on the basis of ascer- tained facts as to whether the outcome will be good, bad or indifferent. Hence many kinds of weird activities and propaganda flourish like the proverbial bay tree. Of all organized activities looking towards the direct modification of the environment to the benefit of mankind, that group comprised under the terms sanitation, hygiene NATURAL DEATH, PUBLIC HEALTH 229 and public health have, by all odds, the best case when measured in terms of accomplishment. Man’s expecta- tion of life has increased as he has come down through the centuries (cf. Pearson and Macdonell.) A large part of this improvement must surely be credited to his improved understanding of how to cope with an always more or less inimical environment and assuage its asper- ities to his greater comfort and well-being. To, fail to give this credit would be manifestly absurd. But it would be equally absurd to attempt to main- tain that all decline in the death-rate which has occurred has been due to the efforts of health officials, whether conscious or unconscious, as is often asserted and still more often implied in the impassioned outpourings of zealous propagandists. The open-minded student of the natural history of disease knows perfectly well that a large part of the improvement in the rate of mortality cannot possibly have been due to any such efforts. To illustrate the point, I have prepared a series of illustra- tions dealing with conditions in the Registration Area of the United States in the immediate past. All these diagrams (Figures 52, 53, and 54) give death-rates per 100,000 from various causes of death in the period of 1900-1918, inclusive, both sexes for simplicity being taken together. The lines are all plotted on a logarithmic scale. The result of this method of plotting is that the slope trend of each line is directly comparable with that of any other, no matter what the absolute magnitude of the rates concerned. It is these slopes, measuring im- provement in mortality, to which I would especially direct attention. 230 BIOLOGY OF DEATH CONTROLLABLE CAUSES OF DEATH 4000 100 -— 9 = = “Sevezise: a s SN eee = = “Dire ewes eseen lm, wv THER Lg AND Senco i CROUp Nr 10 — Wy a Nem eoo~™ kK — ~~ ao Ly. < ‘iniiead & = SENV7Epy SNe 7 S vy Q ‘— pe ph OS ee ad a ed 190001 02 03 04 05 060708 09 10 II 2 3 4 IS 16 17 1B YEAR a Fria. 52.—Trend of death rates for four causes of death against which public health activities ave been particularly directed. In figure 52 are given the trends of the death-rates for four diseases against which public health and sani- tary activities have been particularly and vigorously NATURAL DEATH, PUBLIC HEALTH _ 231 directed, with, as we are accustomed to say, most grati- fying results. The diseases are: Tuberculosis of the lungs. Typhoid fever. Diphtheria and croup. Dysentery. We note at once that the death-rates from these diseases have all steadily declined in the 19 years under review. But the rate of drop has been slightly unequal. Remembering that the slopes are comparable, where- ever the lines may lie, and that an equal slope means a relatively equally effective diminution of the mortality of the disease, we note that the death-rate from tuber- culosis of the lungs has decreased slightly less than any of the other three. Yet it may fairly be said that so strenuous a warfare, or one engaging in its ranks so many earnest and active workers, has probably never in the history of the world been waged against any disease as that which has been fought in the United States against tuberculosis in the period covered. The rates of decline of the other three diseases are all practically identical. Figure 53 shows entirely similar trends for four other causes of death—namely: ae ae ee Bronchitis (acute and chronic). Paralysis without specified cause. Purulent infection and septicemia. Softening of the brain. Now it will be granted at once, I think, that public health and sanitation can have had, at the utmost, ex- tremely little, if anything, to do with the trend of mor- tality from these four causes of death. For the most part they certainly represent pathological entities far beyond the present reach of the health officer. Yet the a Ne 232 BIOLOGY OF DEATH NON - CONTROLLED CAUSES _OF DEATH 1000 — 100 |~ ©}. = SF Ws Gy, a ff. SSS eute ong 8 ba Mage -< ibiia’ 3) Papgy oe. aca oo ty Te ee Sa he i i ic a, ee CT Oe os a 20/7 one Pe ‘yj Ea es =~, COR, Evy CAUSE eenweee” S| po See, os GR <= ee NY 4 me — ae ne Pr Laas iw a Cems a ian = ee 8 so re (a me SR es Ae Us ee 1900 0! 02 03 04 05 06 07 08 OD 10 HH I2 I3 1% 1S 16 17 18 YEAR Fic. 53,—Trend of death rates from four causes of death upon which no direct attempt at control has been made. outstanding fact is that their rates of mortality have de- clined and are declining just as did those in the control- lable group shown in Figure 52. It is of no moment NATURAL DEATH, PUBLIC HEALTH — 233 000 ~— 100 aa 4 Noy cen, S ie st Co, OMR Es terran enen, Qe a 10 a= om Ss = 8 ‘_ els a ee ee oe 1900 O! 02 03 04 05 06 07 08 09 10 Il 12 13 14 18 16 17 18 YEAR Fria. 54.—Trend of combined ae rate from the four causes ona in Figure 52 as compared with the four causes shown in Figure to say that the four causes of death in the second group are absolutely of less importance than some of those in the first group, because what we are here discussing is not relative force of mortality from different causes, 234 BIOLOGY OF DEATH but rather the trend of mortality from particular causes. The rate of decline is just as significant, whatever the absolute point from which the curve starts. It is difficult to carry in the mind an exact impression of the slope of a line, so, in order that a comparison may be made, I have plotted in Figure 54, first, the total rate of mortality from the four controllable causes of death taken together and, second, the total rate of mortality from the four uncontrolled causes taken together. The result is interesting. The two lines were actually nearer together in 1900 than they were in 1918. They have diverged because the recorded mortality from the uncon- trolled four has actually decreased faster in the 19 years than has that from the four against which we have been actively fighting. The divergence is not great, however. Perhaps we are only justified in saying that the mortality in each of the two groups has notably declined, and at not far from identical rates. Now the four diseases in this group, I chose quite at random from among the causes of death whose rates I knew to be declining, to use as an illustration solely. I could easily pick out eight other causes of death which would illustrate the same point. I do not wish too much stress to be laid upon these examples. If they may serve merely to drive sharply home into the mind that it is only the tyro or the reckless propagandist, long ago a stranger to truth, who will venture to assert that a declining death- rate in and of itself marks the successful result of human effort, I shall be abundantly satisfied. It has been objected that the decline shown by the four ‘‘non-controlled’’ causes in the example just dealt with is due wholly, or nearly so, to changes in the practice of physicians relative to the reporting of the cause of NATURAL DEATH, PUBLIC HEALTH ~— 2385 death, and that, therefore, the decline is spurious. I have not been able to find that there is any good evidence that this is the fact; that, in short, changes in reporting prac- tice have affected the ‘‘non-controlled’’ group more than the ‘‘controllable’’ group. But another kind of example may be cited to illustrate the same general point. Suppose we compare the course of mortality from certain well- defined causes, about the reporting of which there can be no controversy, in (a) a group of countries standing in an advanced position in matters of public health, sanitation, etc., and (b) a group of countries relatively backward and undeveloped in these respects. Such a comparison is im- possible to make over any long period of time because of lack of comparable data. I have succeeded in getting com- parable statistics on two diseases, namely typhoid fever and diphtheria, for the period 1898 to 1912 inclusive, for the following countries: A. Countries having (in period B. Countries having (in period covered) highly developed covered) less highly developed public health and sanitation. public health and sanitation Australia than those in group A. Austria Italy England and Wales Jamaica Germany Roumania Without going into detailed comparisons, which might be thought invidious, it is evident on the face of the case, I think, that the countries in the A group were, on the average during the period covered, much more advanced in all practical public health matters than were the coun- tries in group B. In Figures 55 and 56 are shown the trends of the weighted average death rates from typhoid fever and diphtheria respectively in the two groups of countries. It is evident from these diagrams that the death rates 236 BIOLOGY OF DEATH from these two causes declined, during the period cov- ered, in both the A and the B groups of countries and at not far from the same rate. There is no such large difference as would be expected if organized human inter- ference with the natural history of disease always played 100 TYPHOID FEVER 0, 80, . eee, DEATH RATE | Se TS ae Ce Dee ee 498 99 1900 0! 0@ OF 04 05 OF 06 9 10 Hl 2 YEAR Fig. 55.—Course of the weighted average death rate, for the countries in the A (solid line) and B (broken line) groups, from typhoid fever. the réle of immediate and large importance which the propagandist asserts that it does. To guard against the possibility of any misunder- standing, let me say quite specifically and categorically, that the above is not intended in any way to convey the idea that public health work is not desirable, or that a NATURAL DEATH, PUBLIC HEALTH 287 laissez-faire policy would be better, or that public health efforts have not been enormously valuable in connection with typhoid fever and diphtheria. My purpose is quite other, being solely a desire to emphasize two things, viz: 1. That the trend of human mortality in time is an 400 90 80 70 -- OIPHTHEPIA 30;— DEATH RATE cou % fl} = 0 — a5 BSB ss ee Ee ei ea 1 7 YEAR Fig. 56.—Like figure 55, but for diphtheria and croup. extraordinarily complex biological phenomenon, in which many factors besides the best efforts of health officials are involved. 2. That for many causes of death a vast lot needs to be added to our knowledge of etiology, in the broadest sense, before really efficient control can be hoped for. This knowledge can come only through scientific investi- 238 BIOLOGY OF DEATH gation, and not through the complacent acceptance of the propagandist’s assurance that ‘‘if what knowledge we now have is applied, all will be well.’’* Many others have, of course, perceived that, in the natural history of disease, mortality from particular causes may decline over long periods of time without any relation to what health departments have done, or tried to do about it. For example, Given has recently pointed out that there is no evidence that anything that man has done has affected, in either one way or the other, the decline in the mortality of tuberculosis, which has been continuous for nearly three-quarters of a century. Pearson has discussed the same point. There is much in our public health work that is worthy of the highest praise. When based upon a sound founda- tion of ascertained fact it may, and does, proceed with a step as firm and inexorable as that of Fate itself, to the wiping out of preventable mortality. Two recent ex- amples may be cited here, by way of specific illustration of what real and reasonably complete scientific knowledge can accomplish in public health work. Both examples are taken from the work of the International Health Board of the Rockefeller Foundation, with the permission of its director, Mr. Wickliffe Rose. The first concerns malaria. The life cycle of the malaria parasite is definitely known, and furnished a * One can but wonder if the many scientific men, who permit, and to some extent approve, such assertions, have ever thought of the menace to the continued support of research in science in general which inheres in this attitude of mind. The support of research comes finally back always to society in general—to the “average citizen” in short. Is it the part of wisdom to leave his education as to the meaning and significance of science for his happiness and well-being, so entirely in the hands of the propagandist as we now do? Has anti-vivisection taught no lesson? NATURAL DEATH, PUBLIC HEALTH — 239 definite scientific basis for control procedure. ‘‘It is well understood, not only by scientists, but also by intel- ligent laymen, that the spread of the infection may be prevented by mosquito control, by protecting people from being bitten by mosquitoes, or by destroying the parasite in the blood of the human carrier. It has been shown, moreover, by repeated demonstrations, that by applica- tion of any one of these measures, or of any combination of them, the amount of malaria in a community may be reduced indefinitely. There are few diseases that pre- sent so many vulnerable points of attack and none per- haps the control of which may be made more definite or certain.’’ (Rose). In 1916 the International Health Board undertook some experiments in control at Crossett, Ark. In des- eribing the work Rose says: “Effort has been made to test the feasibility of malaria control in small communities by resort to such simple anti-mosquito measures as would fall within the limits of expenditure that such communities might well afford. The habits of the three mosquitoes—A. quadrimaculatus Say, A. punctipennis Say, and A. cruzians Wiedermann—which are responsible for the infection in these communities have been made the subject of constant study with a view to eliminating all unnecessary effort, and thereby reducing cost. “Experiment at Crossett, 1916—The first of these tests was undertaken at Crossett, a lumber town of 2,129 inhabitants, situated in Ashley County in south-eastern Arkansas, about 12 miles north of the Louisiana line. Crossett lies at the edge of the so-called “uplands,” in a level, low-lying region (elevation 165 feet), with sufficient undulation to provide reason- ably good natural drainage. Climatic conditions and abundant breeding places favor the propagation of anopheles. Malaria, in its severe form, is widely prevalent as an endemic infection, and according to the estimate of local physicians, is the cause of about 60 per cent. of all illness through- out the region. Within the town itself the malaria rate was high, and was recognized by the lumber corporation and the people as a serious menace to health and working efficiency. “The initial step in the experiment was a survey of the community to determine the malaria incidence, to ascertain in the species of mosquitoes 240 BIOLOGY OF DEATH responsible for the spread of the infection, and to locate the breeding places of these mosquitoes. Breeding places were exhibited on a community map, and organized effort was centered on their destruction or control. The program of simple measures excluded all major drainage. Barrow pits and shallow ponds were filled or drained; streams were cleared of undergrowth when necessary to let the sunlight in; their margins and beds were cleared of vegetation and obstruction; and they were trained to a narrow channel, thus providing an unobstructed off-flow. Artificial ,con- tainers were removed from premises; water barrels on bridges were treated with nitre cake. All remaining breeding places were regularly treated by removing vegetation, opening up shallow margins to give free access to small fish, and spraying once a week with road oil by means of automatic drips or a knapsack sprayer. All operations were under the supervision of a trained lay inspector. Care was exercised to eliminate all unnecessary effort and to secure, not the elimination of the last mosquito, but a rea- sonably high degree of control at a minimum cost.” The results are shown in Figure 57, as measured by a number of physicians’ calls for the treatment of ma- laria in the community. The second example shows the effectiveness of con- trol of yellow fever, another disease for which definite scientific knowledge exists as to etiology and mode of transmission. Nothing could more convincingly demonstrate than does Figure 58 the effectiveness with which this disease can be controlled. The diagram shows the results of the International Health Board’s yellow fever work in Guayaquil in 1918-1920. THE POPULATION PROBLEM Turning to another phase of the problem, it is appar- ent that if, as a result of sanitary and hygienic activi- ties and natural evolution, the average duration of human life is greater now than it used to be and is getting greater all the time, then clearly there must be more people on the earth at any time, out of a given number NATURAL DEATH, PUBLIC HEALTH 241 Malaria Control! at CROSSETT -ARKANSAS Calls for Malaria 1915 1916 (917 1918 e rs fe : 2 9a0)| x $90 = Flllre Oe i 5 ne s Bs als SSS RR tal | 5) wee SREC REE COREL EEE EESEEEREE Ss} fulsd lc at tu : ANRIGETNRipst ENTS eT Monthly. Distribution of Calls Population, 2029 19S 1916 (1918 | Total Calls 1915 2500 YAN. 45 40 6 3 ie ?- 741 FEB. 45 39. 7 2 maRcH = SO) 59 13 4 LEE 200 APRIL 60 8} 12 8 918 - 73 MAY 80 4 3! 2 we 120 98 15 6 | Percentage o: R 1915-1918 i ines *66 a = eduction, Ce 9). 97.1 Aus. 350 ol 33 7 | Per Capita Cost: SEPT. 500 54 22 " 916 = 124 pocr ¢00 46 14 8 1917 63 Nor. 350 20 23 7 igh a: a Lane. 100. 4 15 10 Fra. 57.—Record of malaria control by, Anse rapansta measures, Crossett, Ark. 1916-1918, 16 ‘om ose), BIOLOGY OF DEATH 242 OVOP O OOo ooo Mn INN Wad HOU OL OO ool oye 17 S3UNSWIA F—TO¥LNO JO Ws 81 L—9NINNIDIGES 72 43 26) 12 100 90 70}- 3 3 S$3SVO JO 838WNN 20F 10) MONTHS Fia, 58.—Disappearance of yellow fever from Guayaquil, Ecuador, as a result of control measures. (By permission of International Health Board). NATURAL DEATH, PUBLIC HEALTH ~ 243 born, than was formerly the case. It is furthermore plain that if nothing happens to the birth-rate there must eventually be as many persons living upon the habitable parts of the globe as can possibly be supported with food and the other necessities of life. Malthus, whom every one discusses but few take the trouble to read, pointed out many years ago that the problem of popu- lation transcends, in its direct importance to the welfare of human beings and forms of social organization, all other problems. Lately we have had a demonstration on a ghastly gigantic scale of the truth of Malthus’ conten- tion. For, in last analysis, it cannot be doubted that one important underlying cause of the great war, through which we have just passed, was the ever-growing pres- sure of population upon subsistence. Any system or form of activity which tends, by how- ever slight an amount, to keep more people alive at a given instant of time than would otherwise remain alive, adds to the difficulty of the problem of population. We have just seen that this is precisely what our public-health activities aim to do, and in which they succeed in a not inconsiderable degree. But someone will say at once that, while it is true that the death-rate is falling more or less generally, still the birth-rate is falling concomi- tantly, so we need not worry about the population prob- lem. It is evident that if we regard the population problem in terms of world-area, rather than that of any particular country, its degree of immediacy depends upon the ratio of births to deaths in any given time unit. If we examine, as I have recently done, these death-birth ratios for different countries, we find that they give us little hope of any solution of the problem of population 244 BIOLOGY OF DEATH by virtue of a supposed general positive correlation be- tween birth-rates and death-rates. The relation of birth-rate and death-rate changes to population changes is a simple one and may be put this way. If, neglecting migration as we are justified in doing in the war period and in considering the world prob- lem, in a given time unit the percentage 100 Deaths Births has a value less than 100, it means that the births exceed the deaths and that the population is increasing within the specified time unit. If, on the other hand, the per- centage is greater than 100, it means that the deaths are more frequent than the births and that the population is decreasing, again within the specified time unit. The TABLE 29 Percentage of Deaths to Births 77 non-invaded Year departments Prussia Bavaria England and of France Wales 1913 97 per cent. |............6- 58 percent. | 57 per cent. 1914 110 per cent. 66 per cent. 74 per cent. | 59 per cent. 1915 169 per cent. | 101 per cent. 98;per cent. | 69 per cent. 1916 193 per cent. | 117 per cent. | 131 per cent. | 65 per cent. 1917 179 per cent. | 140 per cent. | 127 per cent. | 75 per cent. 1918 198 per cent. | 132* per cent.| 146 per cent. | 92 per cent. 1919 VBE PEriCONes. [si sieisccidurcecscccmnine beaten macnn ace: oles 73 per cent. DO20 sos sesca sce aspuiosui as | ese nade bend bane del aatntal reac oa te 42* per cent. * First three-fourths of year only. ratio of deaths to births may be conveniently designated as the vital index of a population. From the raw data of births and deaths, I have cal- culated the percentage which the deaths were of the births for (a) the 77 non-invaded departments of France; (b) NATURAL DEATH, PUBLIC HEALTH = 245 Prussia; (c) Bavaria; and (d) England and Wales, from 1913 to1920 by years. The results are shown in Table 29. The points to be especially noted in Table 29 are: 1. In all the countries here dealt with the death-birth ratio in general rose throughout the war period. This means that the proportion of deaths to births increased so long as the war continued. 2. But in England it never rose to the 100 per cent. mark. In other words, in spite of all the dreadful effects of war, England’s population wen on making a net increase throughout the war. 3. Immediately after the war was over, the death- birth ratio began to drop rapidly in all countries. In England in 1919 it had dropped back from the high figure of 92 per cent. in 1918 to 73 per cent. In France it dropped from the high figure of 198 in 1918 to 154 in 1919, a lower figure than France had shown since 1914. In all the countries the same change is occurring at a rapid pace. Perhaps the most striking possible illustration of this is the history of the death-birth ratio of the city of Vienna, shown in Figure 4, with data from the United States and England and Wales for comparison. Prob- ably no single large city in the world was so hard hit by the war as Vienna. Yet observe what has happened to its death-birth ratio. Note how sharp is the decline in 1919 after the peak in 1918. In other words, we see how promptly the growth of population tends to regulate itself back towards the normal after even so disturbing an upset as a great war. In the United States, the death-birth ratio was not affected at all by the war, though it was markedly altered by the influenza epidemic. The facts are shown in Fig- ure 59 for the only years for which data are available. 246 BIOLOGY OF DEATH The area covered is the United States birth registration area. We see that with the very low death-birth ratio of 56 in 1915, there was no significant change till the influenza year 1918, when the ratio rose to 73 per cent. Cor 225 \ 200 Fi \ [73 f ) zl, 7 Re 125 v4 g fe 700 . 8 Rg 7S ener ort oe es ee ee ~ oor | ae a ~y ‘ey [ONTED STATES ~, SO A) @ 912 Ee) Shee 6S OH 7 oe wie 1920 YEAR Fia. 59.—Showing the change in percentage which deaths were of births in each of the years 1912 to 1919 for Vienna ( ); 1915 to 1919 for the United States (—— —); and 1912 to 1920 for England and Wales(. ). But in 1919, it promptly dropped back to the normal value of 57.98, almost identical with the 1917 figure of 57.34. In England and Wales, the provisional figure indi- eates that 1920 will show a lower value for the vital index than that country has had for many years. So we see that neither a highly destructive war, nor the most destructive epidemic since the Middle Ages, serves more than to cause a momentary hesitation in the steady onward march of population growth. NATURAL DEATH, PUBLIC HEALTH _ 247 The first thing obviously needed in any scientific approach to the problem of population is a proper mathe- matical determination and expression of the law of popu- lation gtowth. It has been seen: that the most devastating calamities make but a momentary flicker in the steady progress of the curve. Furthermore, population growth is plainly a biological matter. It depends upon, in last analysis, only the basic biological phenomena of fertility and mortality. To the problem of an adequate mathe- matical expression of the normal growth of populations, my colleague, Dr. Lowell J. Reed, and I have addressed ourselves for some time past. The known data upon which we have to operate are the population counts given by successive censuses. Various attempts have been made in the past to get a mathematical representation of these in order to predict successfully future populations, and to get estimates of the population in inter-censal years. A noteworthy attempt of this sort is Pritchett’s fitting of a parabola of the third order to the United States popu- lation from 1790 to 1880 inclusive. This gave a fairly good result over the period, but was obviously purely empirical, expressed no real biological law of change, and in fact failed badly in prediction after 1890. We have approached the problem from an a priori basis, set up a hypothesis as to the more important biological factors involved, and tested the resulting equation against the facts for a variety of countries. The hypothesis was built up around the following considerations: 1. In any given land area of fixed limits, as by political or natural boundaries, there must necessarily be an upper limit to the number of persons that can be sup- ported on the area. To take an extreme case, it is obvious 248 BIOLOGY OF DEATH that not so many as 25,000 persons could possibly stand upon an acre of ground, let alone live on it. So, similarly, there must be for any area an upper limiting number of persons who can possibly live upon it. In mathematical terms this means that the population curve must have an upper limiting asymptote. 2. At some time in the more or less remote past the population of human beings upon any given land area must have been nearly or quite zero. So the curve must have somewhere a lower limiting asymptote. 3. Between these two levels we assume that the rate of growth of the population, that is, the increase in numbers in any given time unit, is proportional to two things, namely: a. The absolute amount of growth (or size of population) already attained ; b. The amount of as yet unutilized, or reserve, means or sources of subsistence still available in the area to support further population. These hypotheses lead directly to a curve of the form shown in Figure 60, in which the position of the asymp- totes and of the point of inflection, when the population is growing at the most rapid rate, are shown in terms of the constants. It is seen that the whole ‘history of a population, as pictured by this curve, is something like this: In the early years following the settlement of a country the population growth is slow. Presently it begins to grow faster. After it passes the point where half the available resources of subsistence have been drawn upon and utilized, the rate of growth becomes slower, until finally the maximum population which the area will support is reached. NATURAL DEATH, PUBLIC HEALTH 249 This theory* of population growth makes it possible to predict what the maximum population in a given area will be, and when it will be attained. Furthermore, one can tell exactly when the population is growing at the maximum rate. To test the theory, we have only to fit g* wre c 4 fn . 2. 2c ee ai | ee | . Fia. 60.—Showing a theoretical curve of population growth. this theoretical curve to the known facts of population for any country by appropriate mathematical methods. If the hypothesis fits well all the known facts for a variety of countries in different stages of population growth, it may well be regarded as a first approximation to a sub- stantially correct hypothesis and expressive of the bio- logical law according to which population grows. In making this test the statistician has somewhat the same * The mathematical hypothesis here dealt with is essentially the same as that of Verhulst, put forth in 1844. As Pearl and Reed pointed out in their first paper on the subject it is a special case of a much more general law. A comprehensive general treatment of the problem we are publishing shortly in another place. The generalization in no way alters the conclusions drawn here from a few illustrative examples. 250 BIOLOGY OF DEATH kind of problem that confronts the astronomer calculat- ing the complete orbit of acomet. The astronomer never has more than a relatively few observations of the posi- 87.274 ——= on 5 UNITED STATES g 150 a 3 y = 2s / z / Zz 10 / = : 8 $0 25 T0020" 4060 80 B00 20 40 60 80 100 20 4060 G0 200020 40 60 80 B00 YEARS Fig. 61.—Showing the curve of growth of the pepilation of the United States. For further explanation of this and the two following diagrams, see text. tion of the comet. He has, from Newtonian principles, a general mathematical expression of the laws of motion of heavenly bodies. He must then construct his whole curve from the data given by the few observations. So, similarly, the statistician has but a relatively few popu- lation observations because census taking has been prac- tised along present lines only a little more than a century. According to the stage in historical development of the country dealt with, he may have given an early, a late, or a middle short piece of the population ‘‘orbit’’ or his- tory. From this he must construct, on the basis of his general theory of ‘‘population orbits,’’ the whole history, past and future, of the population in question. To demonstrate how successful the population curve shown in Figure 60 is in doing this, three diagrams are presented, each illustrating the growth of the population NATURAL DEATH, PUBLIC HEALTH _~ 251 in a different country. The heavy solid portion of each curve shows the region for which census data exist. The lighter broken part of the curve shows the portions out- side this observed range. The circles show the “actual, known observations. The first curve deals with the popu- 41.360 —_—— oat 3 FRANCE 7 POPULATION IN MILLIONS Fia. 62.—Showing the curve of growth of the population of France. lation of the United States. Here the observations come from the first part of the curve, when the population was leaving the lower asymptote. First should be noted the extraordinary accuracy with which the mathematical theory describes the known facts. It would be extremely difficult, by any process, to draw a curve through the ob- served circles and come nearer to hitting them all than this one does. Before considering the detailed consequences of this United States curve in relation to the whole population history of the country, let us first examine some curves for other countries, where the observed data fell in quite different portions of the ‘‘population orbit.’’ Figure 62 252 BIOLOGY OF DEATH gives the curve for France. Since before the time when definite census records began, France has been a rather densely populated country. All the data with which we had to work, belong therefore, towards the final end of the whole population history curve. The known popula- tion data for France and for the United States stand at opposite ends of the whole historical curve. One is an old country whose population is nearing the upper limit; the other a new country whose population started from near the lower asymptote only about a century and a half ago. But it is seen from the diagram that the general theory of population growth fits perfectly the known facts regarding F'rance’s population.in the 120 years for which records exist. While there are some irregularities in the observation, due principally to the effects of the Franco- Prussian war, it is plain that on the whole it would be practically impossible to get a better fitting line through the observational circles than the present one. We have seen that the general theory of population describes with equal accuracy the rate of growth in a young country, with rapidly increasing population, and an old country, where the population is approaching close to the absolute saturation point. Let us now see how it works for a country in an intermediate position in respect of population. Figure 63 shows the population history of Serbia. Here it will be noted at once that the heavy line, which denotes the region of known census data, lies about in the middle of the whole curve. Again the fit of theory to observation is extraordinarily close. No better fit, by a general law involving no more than 3 con- stants, could possibly be hoped for, I think that these three examples, which could be multiplied to include practically every country for which NATURAL DEATH, PUBLIC HEALTH 253 accurate population data exist, furnish a cogent demon- stration of the essential soundness and accuracy of this . theory of population growth. Indeed, the facts warrant, I believe, our regarding this as a first approximation to the true natural law of population growth. We now are 4.388 ral - / = SERVIA / POPULATION IN MILLIONS 0 60 & 200020 40 @ & 200 YEARS Fie. 63.—Showing the curve of growth of the_population of Serbia. approaching the proper mathematical foundation on which to build sociological discussions of the problem of population. As a further demonstration of the soundness of this theory of population growth, let attention be directed for a moment to an example of its experimental verification. To a fruit fly (Drosophila) in a half pint milk bottle, such as is used in experimental work on these organisms, the interior of the bottle represents a definitely limited uni- verse. How does the fly population grow in such a uni- verse? We start a bottle with a male and female fiy, and a small sample, say 10, of their offspring of different ages (larve and pupe). The results are shown in Fig- 254 BIOLOGY OF DEATH ure 64. The circles give the observed population growth, obtained by census counts at 3-day intervals. There can be no doubt that this population has grown in accordance with the equation. The two final observations lie below the curve, because of the difficulty experienced, in this 846.14 re ° 900 275 * a GROWTH OF DROSOPHILA POPULATION f 228 oe VA 3 Z 1 "4 _f +80 2 125 Fa ice h. L. a. se Pe ss ; 2 i ¢ 2 75 zw 7) r 7 7 OT. NON Fie. 64.—Showing the growth of a Drosophila population kept under controlled experimental conditions. particular experiment, of keeping the food supply in good condition after so long a period from the start. Let us return to the further discussion of the popu- lation problem of the United States in the light of the curve. The first question which interests one is this: When did or will the population curve of this country pass the point of inflection and exhibit a progressively diminishing instead of increasing rate of growth? It is easily deter- mined that this point occurred about April 1, 1914, on the assumption that our present numerical values reliably rep- resent the rate of population growth in this country. In other words, so far as we may rely upon present nu- merical values, the United States has already passed its period of most rapid population growth, unless there NATURAL DEATH, PUBLIC HEALTH 255 comes into play some factor not now known, and which has never operated during the past history of the country, to make the rate of growth more rapid. The latter con- tingency appears improbable. The 1920 census confirms the result, indicated by the curve, that the period of most rapid population growth was passed somewhere in the last decade. The population at the point of inflection works out to have been 98,637,000, which was, in fact, about the population of the country in 1914. The upper asymptote given by the equation has the value of 197,274,000 roughly. This means that the maxi- mum population which continental United States, as now areally limited, will have, will be roughly twice the pres- ent population; provided no fundamental new factor comes into play in the meantime, different in its magni- tude and mode of operation from any of the factors which have influenced population growth in the past. This state of affairs will be reached in about the year 2,100, a little less than two centuries hence. Perhaps it may be thought that the magnitude of this number is not suffi- ciently imposing. It is so easy, and most writers on population have been so prone, to extrapolate population by geometric series or by a parabola or some such purely empirical curve, and arrive at stupendous figures, that calm consideration of real probabilities is most difficult to obtain. While we regard the numerical results as only a rough first approximation, it remains a fact that if anyone will soberly think of every city, every village, every town in this country having its present population multiplied by 2, and will further think of twice as many persons on the land in agricultural pursuits, he will be bound, we think, to conclude that the country would be 256 BIOLOGY OF DEATH fairly densely populated. It would have about 66 per- sons per square mile of land area. It will at once be pointed out that many European countries have a much greater density of population than 66 persons to the square mile, as, for example, Belgium with 673, the Netherlands with 499, etc. But it must not be forgotten that these countries are far from self- supporting in respect of physical means of subsistence. They are, or were before the war, economically self- supporting, which is a very different thing, because, by their industrial development at home and in their colo- nies, they produce money enough to buy physical means of subsistence from less densely populated portions of the world. We can, of course, do the same thing, pro- vided that by the time our population gets so dense as to make it necessary, there still remain portions of the globe where food, clothing material and fuel are produced in excess of the needs of their home populations. Now 197,000,000 people will require, on the basis of our present food habits, about 260,000,000 million calories per annum. The United States, during the seven years 1911-1918, produced as an annual average, in the form of human food, both primary and secondary (i.e., broadly vegetable and animal), only 137,163,606 million calories per year. So that, unless our food habits radically change, and aman is able to do with less than 3,000 to 3,500 calories per day, or unless our agricultural production radically increases, which it appears not likely to do for a variety of reasons which cannot be here gone into, it will be necessary, when even our modest figure for the asymptotic population is reached, to import nearly or quite one-half of the calories necessary for that population. It seems improbable that the population will go on increasing at NATURAL DEATH, PUBLIC HEALTH 257 any very rapid rate after such a condition is reached. East has shown that the United States has already entered _ upon the era of diminishing returns in agriculture in this country. Is it at all reasonable to suppose that by the time this country has closely approached the asymptote here indicated, with all the competition for means of sub- sistence which the already densely populated countries of Europe will then be putting up, there can be found any portion of the globe producing food in excess of its own needs to an extent to make it possible for us to find the calories we shall need to import? Altogether we believe it will be the part of wisdom for anyone disposed to criticize our asymptotic value of a hundred and ninety-seven and a quarter millions because it is thought too small, to look further into all the rele- vant facts. This point of view is sustained in a recent paper by East in which the future agricultural resources of the country are particularly examined. The relation of this already pressing problem of popu- lation to the problem of the duration of life is obvious enough. For every point that the death rate is lowered (or, what is the same thing, the average duration of life increased) the problem of population is made more imme- diate and more difficult unless there is a corresponding decrease in the birth-rate. Is it to be wondered at that most thoughtful students of the problem of population are advocates of birth control? Or is it remarkable that Major Leonard Darwin, president of the Eugenics Education Society in England, should say in a carefully considered memorandum to the new British Ministry of Health: ‘‘In the interests of posterity it is most desirable that parents should now limit the size of their families by any means held by them to be right (provided such 17 258 BIOLOGY OF DEATH means are not injurious to health, nor, like abortion, an offense against public morals) to such an extent that the children could be brought up as efficient citizens and with- out deterioration in the standards of their civilization; and that parents should not limit the size of the family for any other reasons except on account of definite hered- itary defects, or to secure an adequate interval between births.’’ I am able to make no prediction as to how civilized countries will solve (if they do solve) the problems arising out of the impending saturation with human popu- lation of the portion of the earth’s surface habitable by man. The certainty and assurance with which various ones of my friends advance solutions excites my wonder and admiration. But what impresses me even more is that scarcely any two of them agree on the nature of the panacea. To some it is birth control, to others synthetic foods derived from the atmosphere or else- where, and so on. For myself, I am content if I have succeeded, in even a smal] measure, in indicating that population growth pre- sents a problem fast becoming urgent; a problem that in its overwhelming significance and almost infinite rami- fications touches upon virtually every present human ac- tivity and interest, and in particular upon the activities comprised in the terms public health and hygiene. BIBLIOGRAPHY The following list of literature in no sense aims at completeness within the field covered. It is, in the main, made up only of the sources which have been consulted in the preparation of the present volume. It is hoped, however, that even with this limitation it may serve as a useful introduction to the literature for any who may wish to pursue further their reading on the subjects here dealt with. Amma, K. Uher die Differenzierung der Keimbahnzellen bei den Kope- poden. Arch. f. Zellforsch, Bd. VI, 1911, BaTaLton. La parthenogenese experimentale des amphibiens. Rev. gen. d. Sci. T. XXII, p. 786, 1911. See also Comp. rend. Acad. Sci. Paris, T. CL, 996, 1910; T. CLII, 920,-1911; T. CLII, pp. 1120 and 1271, 1911; T. CLVI, 812, 1913; Arch. de Zool. exper. et gen., T, XLVI, p. 103, 1910. BEETON, M. and Pearson, K. Data for the problem of evolution in man. II.—A first study of the inheritance of longevity, and the selective death rate in man. Proc. Roy. Soc. Vol. LXV, pp, 290-305, 1899. Breeton, M. and Pearson, K. On the inheritance of the duration of life, rand on the intensity of natural selection in man. Biometrika, Vol. 1, pp. 50-89, 1901. Bett, A G. 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INDEX Acanthias, 38 Accidental deaths, 107 Activity, metabolic, 211-217 Agamic reproduction, 33, 35, 37, 41, 17 Alchemy, 19 Alimentary tract, 107, 108, 110, 112, 129-131 Amicronucleate races, 72, 73 Amma, K., 39, 259 Amphibia, longevity of, 22 Analysis of life tables, 94-101 Animals, longevity of, 22, 68 Anopheles cruzians, 239 punctipennis, 239 quadrimaculbatus, 239 Anti-vivisection, 238 Apple trees, 37, 74, 75 Artificial parthenogenesis, 51-58, 223 Ascaris, 39 Aseptic life, 43, 200-202 Astrology, 19 Australia, 235 Austria, 235 Autogamy, 73 Automobiles, 226 Bacteria, role of, in duration of life, 43, 199-202 Bataillon, 52, 259 Bavaria, 244, 245 Bee, senility in, 28 Beeton, M., 166, 169, 171, 259 Belgium, 256 Bell, A. G., 152-158, 165, 166, 225, 259 Benedict, H. N., 44, 259 Bertillon, J., 216, 259 Bibliography, 259-268 Bills of mortality, 79 Biological classification of causes of death, 104-137 Birds, longevity of, 22, 63 Birth control, 257 injuries at, 121, 123 premature, 121, 123 Blood, 107, 108, 111, 118, 119 Body size and longevity, 26, 68 weight, 68 Bogdanow, E. A., 200, 259 Brain weight, 68 Brazil, 106 Bright’s disease, 161 Bronchitis, 231, 232 Brown, J. W., 206, 261 Brownlee, J., 183 Budding, 37 Bulloch, W., 259 Burrows, M. T., 59-62, 260 Callithria, 68 Calories, 256 Cancer cells, 61 Carrel, A., 10, 61-65, 73, 74, 76-78, 224, 260 Cat, 61 Cattell, J. McK., 10 Causes of death, 102-137 biological classifi- cation of, 104 international clas- sification of, 103 non-controlled, 232, 233 Cells, interstitial, 219 Cellular immortality, 51-78 269 270 Centenarians, 23-26, 64 Cephalic index, 175 Cephalisation, 68 Chances of death, 79-101 Changes in expectation of life, 82-94 Chick, 59-61, 76 duration of life of, 63 Child, C. M., 34-36, 39, 43, 44, 260 Child welfare, 112 Chironomus, 39 Circulatory system, 107, 108, 111, 118, 119 Classification, biological, of causes of death, 104 international, of causes of death, 103 Clocks, analogy with living things, 150, 151, 198 Clonal reproduction, 37, 74 Coefficient of correlation, 168 Coelenterates, 62 Cohnheim, J., 44, 260 Collis, E. L., 216, 260 Conjugation, 30-33, 71, 73 Conklin, E. G., 29, 44, 260 | Controllable causes of death, 230, 233 Correlation coefficient, 168 Correlations in duration of life, 168- 177 Crossett, 239, 241 Croup, 230, 231 Crum, F. S., 184, 260 Culture of tissues in vitro, 58-78 Curve, mortality, graduation of, 94- 101 specific death rate, 114, 116 Curves, logarithmic plotting of, 114 Cyclops, 39 Cytomorphosis, 28 Cytoplasm, 29, 44 Darwin, L., 257 Davis, W. H., 113 Dawson, J. A., 73, 260 INDEX Dawson, M. M., 82, 260 Death, appearance of in evolution, 42 biological classification of eauses of, 104-137 chances of, 79-101 causes of, 102-137 the Marksman, 96-98 theories of, 43-50 Death birth ratio, 243-246 Death-rate, selective, 177-185 Death-rates, crude, 112 specific, 112-137 DeDecker, A., 216, 267 Deer, 68 Delage, Y., 45, 260 Delcourt, A., 200, 260 Descent, method of, 40-42 Diarrhea, 110, 112 Differentiation, 45-47, 67, 75 Diphtheria, 230, 231, 235, 237 Diseases, preventability of, 162 Doflein, F., 33, 260 Dog fish, 39 Domestic fowl, duration of life of, 63 Donaldson, H. H., 29, 260 Drosophila melanogaster, 186-202, 208-211, 214, 222, 225, 226, 253, 254 Dublin, L. I., 82, 113, 260, 261 du Noiiy, P. L., 77 Duration of life, correlation in, 168- 177 experimental study of, 186-222 influence of activi- ty on, 211-217 influence of tem- perature on, 208- 217 inheritance of, 94, 160-185 in man, 79-94, 150- 185 INDEX Duration of life of domestic fowl, 63 of parents and off- spring, 155-157 réle of bacteria in, 43, 199-202 variation in, 21, 22, 68, 80-82 Dysentery, 230, 231 East, E. M., 195, 257, 261 Ebeling, A. H., 60, 61, 74, 76, 77, 78, 260, 261 Ectoderm, 138-149 Effects of public health work, 112, 227-242 Egypt, expectation of life in, 87-89 Elephant, longevity of, 22 Embryology and mortality, 138-149 Embryonic juice, 74 Endocrinal system, 107, 108, 112, 133, 134 Endoderm, 138-149 Endomixis, 30, 33, 71-73 Energy, 213-217 England, 106, 108-111, 139, 140, 235, 244-246 Enriques, P., 73, 261 Environment, 225, 226 Epidemic, influenza, 245 Erdman, R., 30, 261, 268 Eudorina elegans, 31, 73 Eugenics, 227 Education Society, 257 Evolutionary progress in longevity, 87-94 Evolution of ectoderm, 141 of endoderm, 141 of mesoderm, 141 of workmanship of, 148 Excretory organs, 107, 108, 111, 126, 127 Exercise, 212, 213 Expectation of life, defined, 82 changes in, 82-94 271 Expectation of life, effect of selection on, 94 hypothetical, 164 in ancient Egypt, 87-89 in ancient Rome, 90-92 in Hispania and Lusitania, 91- 92 in Roman Africa, 92-93 Experimental study of duration of life, 186-222 Eye color, 174, 175 Fermat, 82 Fertilizin, 57 Fish, longevity of, 22 Fisher, A., 101, 149, 184, 261 Fisher, I., 161, 162, 165 Fission, 32, 33, 35, 40, 41 Fitting the mortality curve, 94-101 Food requirements, 256 Forsyth, C. H., 161, 164, 261 Fowl, duration of life of, 63 France, 244, 245, 251, 252 Franco-Prussian war, 252 Fraternal correlations, 171, 172, 175, 176 Friedenthal, H., 68, 69, 261 Friends’ Provident association, 167 Frog, 52, 58, 59 Galvani, 58 Genealogy of Hyde family, 152 Genetic variation, 190 Germany, 235 Germ cells, 37-42, 51-58 layers, 138 plasm, 227, 228 Given, D. H. C., 238, 261 Gland, pituitary, 220-222 Glands, puberty, 217-219 272 Glaucoma pyriformis, 73 Glover, J. W., 80, 84, 88, 90-92, 261 Gonads, 217-219 Gonococeus infection, 123, 124 Graduation of mortality curve, 94- 101 Grafting, 37 Graunt, J., 79 Greenwood, M., 205, 216, 259-261 Groth, 205, 261 Growth of Drosophila population, 254 of populations, 247-258 Growth of United States, 250-252, 254-257 Guayaquil, 240, 242 Guinea pig, 61 Guyénot, E., 200, 260, 261 Guyer, M. F., 52, 262 Hahn, 205, 261 Halley, E., 81, 82, 84, 262 Harper, M., 39, 262 Harrison, R. G., 58-60, 63, 64, 224, 262 Hartman, M., 31, 73, 262 Heart muscle, 61 Hegner, R. W., 40, 262 Henderson, R., 99, 262 Heron, D., 206, 262 Hersch, L., 202, 203, 205, 206, 208, 262 Hertwig, R., 44, 263 Hispania and Lusitania, expectation of life in, 91-92 Hodge, C. F., 27, 28, 263 Holland, 184 Homicide, 107 Homoiotoxin, 64 Howard, W. T., 44, 263 Hyde family, 152-166 Hyde, R. R., 198, 225, 263 Hygiene, 227 INDEX Immortality, cellular, 51-78 human, 17-20 of protozoa, 30-33, 64 of somatic cells, 58-78 Industrial mortality, 216 Infant mortality, 205, 206, 208 Influence of activity on duration of of life, 211-217 of, poverty on mortality, 202-208 of serum on tissue cul- tures, 76, 77 of temperature on dura- tion of life, 208-217 Influenza epidemic, 245 Inheritance of duration of life, 94 in Droso- phila, 186-198 in man, 150-185 of physical characters, 174, 175 Injuries at birth, 121, 123 Insects, longevity of, 22 Internationa] classification of causes of death, 103 Health Board, 240, 242 Interstitial cells, 219 Invertebrates, longevity of, 22 In vitro culture of tissues, 58-78 Italy, 235 238- Jamaica, 235 Jennings, H. §., 31, 33, 40, 41, 45, 71, 72, 263 Jickeli, C. F., 44, 263 Jollos, 33, 263 Jones, D. F., 261 Kassowitz, M., 44, 263 Keimbahn, 40 Kidneys, 61, 107, 108, 111, 126, 127 INDEX Kopf, E. W., 113, 260 Korschelt, E., 263 Landed Gentry, 167, 169, 172 Lankaster, E. R., 263 Levasseur, E., 82, 263 Legrand, M. A., 263 Lewis, M. R., 62, 263 Lewis, W. H., 53, 54, 62, 263, 264 Life, aseptic, 43, 200-202 changes in expectation of, 82-94 curve of Hyde family, 153 cycle of Drosophila, 187, 188 prolonging, 17, 54, 218, 221 table, 79-82 analysis of, 94-101 Breslau, 83, 84, 92 Carlisle, 83, 86 U. S., 1910, 83-86 Lillie, F. R., 57, 263 List, International, 103 Locomotor ataxia, 124 Loeb, J., 47, 52-55, 57, 200, 201, 208- 211, 214, 215, 223, 226, 263, 264 Loeb, L., 59, 64, 65, 67, 224, 264 Logarithmic plotting, 114 London, 205-208 Longevity, body size and, 26 evolutionary progress in, 87-04 of animals, 22 of parents, 158, 160 Lowell Institute, 9, 27 Macdonell, W. R., 87, 89-93, 229, 264 Malaria, 238-241 Malthus, T. R., 243 Mammals, longevity of, 22 Man, longevity of, 23-26, 80-94 Marmoset, 68 Mendelian inheritance, 194, 197, 198 Mesoderm, 138-149 Metabolic activity, 211-217 Metazoa, 31, 33, 40, 46, 71 273 Metchnikoff, E., 43, 109, 200, 264 Method of descent, 40-42 Micronucleus, 72 Minot, C. S., 27, 28, 44, 71, 264 Mitchell, P. C., 264 Mitosis, 61 Montgomery, T. H., 44, 265 Morgan, T. H., 10, 186, 197, 265 Mortality, bills of, 79 curve, graduation of, 94- 101 embryological basis of, 138-149 industrial, 216 infant, 205, 206 influence of poverty on, 202-208 organ system in, 107, 108 Mosquito, 239, 240 Most fatal organ systems, 136 Mouse, 68, 220-222 growth of, 69-70 Miihlmann, M., 44, 265 Miiller, J., 44 Miiller, L. R,, 265 Muscular system, 107, 108, 112, 127, 128 Nascher, I., 26, 27, 265 Nerve cells, senile changes in, 27-29 Nervous system, 107, 108, 130, 131 Netherlands, 256 Non-controlled causes of death, 232, 233 Northrop, J. H., 200, 201, 209-211, 214, 215, 226, 264, 265 Nucleus, 29, 30, 44 Occupation, 216 Ogle, W., 95 Orbits, 250 Organ systems in mortality, 107, 108 most fatal, 136 Oxytricha hymenostoma, 73 274 Paralysis, 231, 232 Paramecium, 30-32, 35, 40, 72 Parental correlations, 171, 172, 174, 176 Parents and offspring, duration of life of, 155-157 longevity of, 158, 160 Paris, 202-206 Parr, T., 24 Parthenogenesis, artificial, 51-58, 223 Pascal, 82 Pearl, R., 106, 201, 225, 249, 265 Pearson, K., 19, 87-91, 93-101, 166, 169-177, 179, 182, 183, 225, 229, 238, 259, 266 Peerage, 167, 169, 172 Pennaria, 62 Physical characters, inheritance of, 174, 175 Pituitary gland, 220-222 Pixell-Goodrich, Mrs., 28 Planaria dorotocephala, 34, 35 Plants, senility in, 44 : Ploetz, A., 178, 179, 182, 183, 225, 266 Population, 240-258 Potassium cyanide, 53, 54 Poverty, 202-208 Premature birth, 121, 123 Preventability of diseases, 162 Pritchett, A. S., 247, 266 Progress, evolutionary, in longevity, 87-94 Prolonging life, 17, 54, 218, 221 Prostate, 126, 219 Protozoa, 30-33, 40, 41, 46 immortality of, 30-33, 41, 64, 71 Prussia, 244, 245 Puberty glands, 217-219 Publie health work, effects of, 112, 227-242 Purulent infection, 231, 232 INDEX Quaker records, 171, 173 Rabbit, 68 Rat, 61, 212, 213, 218 Ratio, death-birth, 243-246 Ray, L. A., 69, 70, 220, 221, 266 Reed, L. J., 247, 249, 266 Registration Area, U. S., 106, 108, 109, 1389, 140, 164, 229, 245, 246 Reproduction, organic, 33, 41 by budding, 37 by fission, 32, 33, 41 clonal, 37 sexual, 37-40, 41 Reptile, longevity of, 22 Respiratory system, 107, 108, 110, 112, 119, 120, 136, 137 Results, summary of, 223-227 Richards, H. A., 86, 87, 266 Ritter, W. E., 75, 266 Robertson, T. B., 69, 70, 220, 221, 266 Rockefeller Foundation, 238 Institute, 52, 61 Role of bacteria in duration of life, 43, 199-202 Roman Africa, expectation of life in, 92 Rome, expectation of life in, 90-92 Romeis, B., 219, 266 Rose, W., 238, 239, 241, 266 Roumania, 235 Roundworm, 39 Royal families, 177 Rubner, M., 213, 214, 226, 267 Saleeby, 183 Sanitation, 227, 235 Sao Paulo, 106, 108-111, 139, 140 Sea urchin, 52, 54, 57 Selection, effect of, on expectation of life, 94 Selective death rate, 177-185 Seneca, 102 INDEX Senescence, 27-30, 46, 70-78 theories of, 43-50 Senile changes in nerve cells, 27-29 Senility as cause of death, 109 in plants, 44, 74, 75 Septicemia, 231, 232 Serbia, 252, 253 Serum, influence on tissue culture, 76, 77 Sex organs, 107, 108, 111, 121-125, 217-219 Sexual reproduction, 37-41 Shell, J., 26, 27 Skeletal system, 107, 108, 112, 127, 128 Skin, 107, 108, 110, 112, 131, 132 Slonaker, J. R., 212, 213, 218, 228, 267 Slotopolski, B., 33, 267 Snow, E. C., 179-183, 225, 267 Softening of the brain, 231, 232 Soma, 40 Somatic cells, immortality of, 58-78 Span, 174, 175 Spiegelberg, W., 87 Spiritualism, 18-20 Spleen, 61 Sponges, 62 Stature, 174, 175 Steinach, E., 217-219, 267 Stenostomum, 35, 36 Stevenson, T. H. C., 206-208, 267 Still births, 205 Strongylocentrotus purpuratus, 55, 56 Summary of results, 223-227 Survivorship lines of Drosophila, 188, 192, 195 Syphilis, 123 275 Table, life, 79-82 Temperature, 208-217 Tethelin, 70, 220-222 Theories of death, 43-50 Theory of population growth, 249 Thyroid gland, 61 Tissue culture in vitro, 58-78 Transplantation of tumors, 64, 65 Tuberculosis, 161, 204, 208, 230, 231, 238 Tumor transplantation, 64, 65 Typhoid fever, 230, 231, 235, 236 United States, growth of, 250-252, 254-257 Urostyla grandis, 72 Van Buren, G. H., 113, 260 Variation, genetic, 190 Venereal diseases, 123, 124 Verhulst, P. F., 249, 267 Verworn, M., 44, 267 Vienna, 245, 246 Voronoff, 217 Waller, A. D., 216, 267. Walworth, R. H., 152, 267 War, 243 Wedekind, 33, 267 Weismann, A., 26, 43, 65, 267 Whale, longevity of, 22 Wilson, H. V., 62, 267 Wittstein, 99 Woodruff, L. L., 30, 33, 72, 73, 267, 268 Woods, F. A., 38, 39, 268 Yellow fever, 240, 242 Young, T. E., 23-25, 268 eT eiaa +t 4 atta {