fj;i^aii;)i:;t5;;^!;;fi;;;:;-;;ji?Hj;- ■ ^ \ * - ' : ;?lfmiv:ii!ii^lfiif!!l|iiif!l!l!i!l !!!l!!fi!rP^^ famous experiment mth 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, ^7"-J'^- — P'PfP of tissue from frog emliryo cultivaf cd in Ivmph, two - ping on tresh plasm ami extract. The preparation shows the extent of growth ol)»ain«'d in Is hours from peripheral cells remaining after extirjiation of t he fraLMiient . (.\fter l.oscc and I^lielinu.) I CONDITIONS OF CELLULAR LMMORTALITY 01 system, the heart, and mesenchymatoiis 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 in vitro of the adult tissues of mammals. He developed a method of culture on a 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 in vitro. Fig-ure 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, etc. Burrows was even able to demonstrate that the isolated heart muscle cells of the chick embrvo can divide as well as differen- tiate, and beat rhythmic ally 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, etc. 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 Yjc, If).— Ptniuuia. Kcstituti.ni muss six days old. completely metamorphosed. «ith developed hydrantlis. Op. perisarc ot original mass; x, perisarc of outgrowth adherent to glass. (From VV ilson.) Fig. 17. — Culture of old strain of connective tissue. 1614 passage. 8 years and S months old, lacking 2 days. 48 hours' growth. x20. (Ebeling). CONDITIONS OF CELLULAR IMMORTALITY G3 strain of connective tissue obtained from a piece of cliick 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. Tliis 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 spealdng 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 vnth. competent observers of poultry. I am quite sure that for most breeds of domestic poultry the normal average expectation of life at hirth 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 BIOLOGYl 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 grqwth 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 transplantations. 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 ordin;ary 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 05 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 immort^al. " 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 inlierent 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 wliich they would attain if they remained in the multicellular body from which they came. Tliis 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 EIOLCGY 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, Avitli 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 CELLUL.\R IMMORTALITY 67 life of these cells in culture to any definite extent. It is not to be expected, of course, that such tissues as hair, or nails, would be capable of independent life, l)ut these are essentially unimportant tissues in the animal econ- omy as compared with those of the heart, the nervous system, the kidneys, etc. 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 cliff ereyitiation and spe- cialization of function of the mutually dependent aggre- gate of cells and tissues ivhich constitute the metazoan body ivhich brings about deaths 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 l)ody 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 liad 68 BIOLOGY OF DEATH ■apon 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 FriedenthaPs 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. ^ , ,. *• r 4. Brain weight Cephalisation factor = ^ ^ , > u j 1 — ^ ^ Total mass of body pT-otoplasm, Now ^Hotal mass of body protoplas^n,^^ 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: ^ , ,. ,. , , Brai n weight Cephalisation factor = .^ , r-r-t ^ ^ (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: 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 (Callithrix) .216 12 years Deer .35 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 overgro\\i:h 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 comiective 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. Longe\dty 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-rWorkers 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 protozoology 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 Oxytriclia 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 hypotrichoua 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, (WoodrufiF, '14), 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 \vith Glaucoina pyriformiSj and those of Hartmann with Eudorina elegans, in which reproduction went on indef- initely with undiminished vigor and no e\^dence 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 deatli), 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 is presumably some chemical combination which, so far, one has supplied only through ** embry- onic juice." An entirelv 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 infinitum. 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 wdth 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 okl one has died— indeed in some cases the shoot has lielped the mortiferous process by the vigorous crowding of youth. In tliis whole picture how fares any idea of the necessity or inevitahleness 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 ynulticellular 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 orgayiization, Tliis 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 tliis 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 abscissae, 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 difi'erence 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 hi^'h concentration of serum had a markedly depressing eflect 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 a wound according to the age of the subject. 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 abscissae. 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 ianimal. 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 sencs- 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 seventeentli 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 Julm 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 onlv at the 79 80 BIOLOGY OF DEATH beginning, however, of its proper matliematical 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 life in 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 Kegistration Area of the United States in 1910 are exhibited in Figure 18, which is based on Glover's United States Life Tables. In tliis table are seen two curved lines, one marked I x and the other dx. The Ix 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 dx 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 h 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 drofjs 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 / , line descends with ever increasing rapidity, until about 90.OCC ^ MILL 3 SI ■ATCS ur C T 'iBLE - fi MO eoooc ^ ^ H — \ \. M£>OC> \ \ \ iCOOO \ — \ V A- * \ \ b; ilo ti X> .\3 60 a? vLA^s 01 urc FiQ. 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 knowai 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 anytliing like the modern fashion was made by the astronomer. Dr. E. Ilalley, 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 \vith which we are here concerned it will be necessary to make use of another function of the mortality table than either the I or dx lines which are shown in Figure 18. I msh 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 e^ denote what is called the curtate expectation of life Ix + lx+l-'r lx+2-^ -\-lx+n ex = -J To a first approximation, sufficiently accurate for our present purposes, the total expectation of life, called e^ , may be obtained from the curtate expectation by the simple relation €l = ex + l/2 THE CHANCES OF DEATH TABLE 6 Changes in expectation oj life from the seventeenth century to the present time 83 Age 0- 1 2 3 4 5 6 7 1- 2- 3- 4- 5- 6- 7- 8 8- 9 9-10 10-11 11-12 12-13 13-14 14-15 15-16 16-17 17-18 18-19 19-20 20-21 21-22 22-23 23-24 24-25 25-26 26-27 27-28 28-29 29-30 30-31 31-32 32-33 33-34 34-35 35-36 36-37 37-38 38-39 39-40 40-41 41-42 42-43 43-44 44-45 45-46 46-47 47-48 48-49 49-50 Average length of life remaining to each one alive at beginning of age interval Breslau, 17th century 33.50 38.10 39.78 40.75 41.25 41.55 41.62 41.16 40.95 40.50 39.99 39.43 38.79 38.16 37.51 36.86 36.22 35.57 34.92 34.26 33.61 32.95 32.34 31.67 31.00 30.38 29.76 29.14 28.51 27.93 27.35 26.76 26 . 18 25.59 25.05 24.51 23.97 23.43 22.88 22.33 21.78 21.23 20.73 20.23 19.72 19.22 18.72 18.21 17.71 17.25 Carlisle, 18th century 38.72 44.67 47.55 49.81 50.76 51.24 51.16 50.79 50.24 49.57 48.82 48.04 47.27 46.50 45.74 44.99 44.27 43.57 42.87 42.16 41.46 40.75 40.03 39.31 38.58 37.86 37.13 36.40 35.68 34.99 34.34 33.68 33.02 32.36 31.68 31.00 30.32 29.63 2S . 95 28.27 27.61 26.97 26.33 25.71 25.08 24.45 23.81 23.16 22.. 50 21.81 U.S. 1910 51.49 57.11 57.72 57.44 56.89 56.21 55.47 54.69 53.87 53.02 52.15 51.26 50.37 49.49 48.60 47.73 46,86 46.01 45.17 44.34 43.53 42.73 41.94 41.16 40.38 39.60 38.81 38.03 37.25 36.48 35.70 34.93 34.17 33.41 32.66 31.90 31.16 30.42 29.68 28.94 28.20 27.46 26.73 25.99 25.26 24.54 23.82 23.10 22.39 21.69 Age 50- 51 51- 52 52- 53 53- 54 54- 55 5.5- 56 56- 57 57- 58 58- 59 59- 60 60- 61 61- 62 62- 63 63- 64 64- 65 65- 66 66- 67 67- 68 68- 69 69- 70 70- 71 71- 72 72- 73 73- 74 74- 75 75- 76 76- 77 77- 78 78- 79 79- 80 80- 81 81- 82 82- 83 83- 84 84- 85 85- 86 86- 87 87- 88 88- 89 89- 90 90- 91 91- 92 92- 93 93- 94 94- 95 95- 96 96- 97 97- 98 98- 99 99-100 Average length of life remaining to each one alive at beginning of age interval Breslau, 17th century 16.81 16.36 15.92 15.48 14.99 14.51 14.02 13.54 13.06 12.57 12.09 11.62 11.14 10.67 10.20 9.73 9.27 8.81 8.36 7.91 7.53 7.17 6.85 6.56 6.25 5.99 5.79 5.71 5.66 5.67 5.74 5.86 6.02 5.85 Carlisle, l-Sth century 21.11 20.39 19.68 18.97 18.27 17.58 16.89 16.21 15.55 14.92 14.34 13.82 13.31 12.81 12.30 11.79 11.27 10.75 10.23 9 9 70 17 8.65 8.16 7.72 7.33 7.00 6.69 6.40 6.11 5.80 5.51 5.20 4.93 4.65 4.39 4.12 3.90 3.71 3.59 3.47 3.28 3.26 3.37 3. 3. 3 3 3 3 2 48 53 53 46 28 07 ,77 U.S.1910 20 98 20.28 19.58 18.89 18.21 17.55 16 16 15 15 14 13 13 12 12 11 90 26 64 03 42 83 26 69 14 60 11.08 10,57 10.07 9,58 9.11 8.66 8 22 7.79 7.38 6,99 6.61 6.25 5.90 5.56 5.25 4.96 4.70 4.45 4.22 4.00 3.79 3.58 3.39 3.20 .03 .87 .73 .59 .47 .35 2 24 2 14 2 04 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 Eegistration 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'5 BRLSLAU 1687- 1691 LIFL TABLE. ^ i 10 Z? "to ti 30 35 40 45 i^ 55 60 63 » TS 30 dS 90 S loO VLAPS OF Lire Pjg 19._Comparing the expectation of life in the 17th century with that of the present time. biologists, Table 6 is inserted, giving the expectations of life from which certain of the diagrams have been plotted. Figure 19 gives the results from Halley's table, based upon the mortality experience in the city of Breslau, in Silesia, during the years 1687 to 1691. This gives us a rough, but in its general sweep sufficiently accurate picture of the forces of mortality towards the end of the seventeenth century From this diagram it appears that at birth the expectation of life of an individual born in Breslau in the seventeenth century was much lower than THE CHANCES OF DEATH 85 that of an individual born in the United States in lUlO. The difference amounts to approximately 18 years! Probably the actual difference was not so great as this, as these early life tables are kno\vn to be inaccurate at the ends of the lifespan, particularly at the beginning. At 10 years of age, the difference in expectation of life had been reduced to just over 12 years; at age 20, to a little less than 10 years ; at age 30 to 7-% years ; at age 50 to just over 4 years; at age 70 to I-V2 years. At age 80 the lines have crossed, but owing to the inade- quate methods, of graduation used by this pioneer actuary, together with the paucity and probably somewhat inac- curate character of his material, no stress is to be laid upon the crossing of the lines, or upon the superior expectation of life at the high ages in the seventeenth century material. What the diagram shows is that the expectation of life at early ages was vastly inferior in the seventeenth century to what it is now, wliile at advanced ages the chances of living were substantially the same. Let us defer the further discussion of the meaning and explanation of this curious fact until we have examined some further data. Figure 20 compares the expectation of life in England at the middle of the eighteenth century, or about a cen- tury later than the last, with present conditions in the United States. Again we see that the expectation at birth was greatly inferior then to what it is now, but the difference is not so great as it was a century earlier, amounting to but 12-3/4 years instead of the 18 we found before. Further it is seen that, just as before, the expec- tations come closer together with advancing age. By the time age 45— middle life— is reached the expectation of life was substantially the same in the eighteenth cen- 86 BIOLOGY OF DEATH tury as it is now. At age 47 the eighteenth century line crosses that for the twentieth century, and with a few trifling exceptions, notably in the years from 56 to 62, the expectation of life for all higher ages was greater then than it is now. We see in the eighteenth century the same kind of result as was indicated in the seven- teenth, only differing in degree. MILA'E'S CARLISLE UdO - 1767 UFZ TABLE ^ h 60 ss so ^5 AO 35 30 ei 20 IS lO r^^ 1 1 1 r— — /* s /I '^ N ^. / N ( ? V^N ^ % N ' ^ ^ N < N "^^ ■^ •v x. ^ ~~~1 nrr 10 H^0a5JO.3S4O4SX>S5606670'JSe0&53035iOO VELARS or UFE Fig. 20 — Comparing the expectation of life in the 18th century with that of the present time. It should be noted that all data as to mortality in the seventeenth and eighteenth centuries lack the degree of accuracy which one desires for purely scientific purposes. By erring generally on the safe side these old mortality tables did well enough for insurance purposes. But quite different results as to the detailed values of life table constants in these early periods are to be found in the literature. For example, Richards constructed some life tables from New England genealogical records, and compared them mth Wiggles worth's table, and also mth those of modern times. His general conclusion, for the THE CHANCES OF DEATH 87 New England population, is: 'Hliat during tho last half- century longevity* in Massachusetts, and probably in New England, has increased, that from 1793 to 1850 the increase is less certain and from the seventeenth to the eighteenth century what data we have point rather to a decrease than to anything else/^ This result may mean any one of a number of things. It may mean merely inadequate and inaccurate data on which the seventeenth century tables were calculated. It may mean a result of less stringent selection in the makeup of the population with the passage of time. In any case it applies only to a small and rather homogeneous group of people. The changes in expectation of life from the middle of the seventeenth century to the present time where the records are most extensive and reliable appear to fur- nish a record of a real evolutionary progression. In this respect at least man has definitely and distinctively changed, as a race, in a period of three and a half cen- turies. This is, of course, a matter of extraordinar\- interest, and at once stimulates the desire to go still farther back in history and see what the expectation of life then was. Fortunately, through the labors of Karl Pearson, and his associate, W. K. Macdonell, it is pos- sible to do this, if not with precise accuracy, at least to a rough first approximation. Pearson has analyzed the records as to age at death which were found upon mummy cases studied by Professor W. Spiegelberg. These mummies belonged to a period between 1,900 and 2,000 years ago, when Egypt was under Eoman dominion. The data were extremely meagre, but from Pearson's analysis of them it has been possible to • Richards somewhat loosely uses this term when he means "expectation of life." 88 BIOLOGY OF DEATH construct the diagram which is shown in Figure 21. Each circle marks a point where it was possible definitely to calculate an expectation of life. The curve running through the circles is a rough graphic smoothing of the scattered observed data. Unfortunately, there were no records of deaths in early infancy. Either there were ^J J 60 r^ 55 1 \ \ SO N \ 45 \ V 1->. 3^ ^ ji '^ " r \ s._ ^ P Co •■^ 25 ^«=; 1 ^ ^ £a^ "^ o X V ■ ^^V. v^ X \ ''J /5 *««2^ -*>.* oo^^ ^ >• to "^- S o • --^ ^ t: ( ? 5 ' 1 S £ z 5- i )0 3 5 4 4 VL 5 t >0 £ > Of 5 e AC O 6 5 •/ V b b 35 90 95 CO Fig. 21. — Comparing the expectation of life of Ancient Egyptians with that of present 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 to a longer remaining duration of life, on the aver- THE CHANCES OF DEATH 80 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 gro\vn 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. Either man is constitution- ally fitter to sur\dve to-day, or he is mentally fitter, i.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 ^\dth 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-Egj^ptians 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 liighest 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 tirst 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 60 r 55 SO ^5 -J 40 U, 35 ^ 15 lO pi \ i ^x^ ^v uNin -D S JATC. J 1 ^< •r ~-t^ s. ^^. "^> ^ »«*•" — ..^ nALC 'f. '^. ^'^'^ ^ ?*x "o-'" ^ k> i_/'s_ ' 1 PCMC ^ N^^ f-^. ^ ^^ fK i^ t^ ""S—-!"^" 10 15 20 Z5 30 35 40 35 "to "SB 53 65 70 75 55 d^J 53 "95 lOO' YEARS OF AGC. Fig. 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 tliird, for those li\dng 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 wliich 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 Ixomano-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 s to P \ a r^ "1 iv UNITED 5 TAIL 5 iO >^ *5 ^ ^ r> AQ V k. 35 ^-^ x^^: 1 ' N, JO x v^ ' , '^^ "^ ^ ^£> N ^ 1 1 * N k i^O rcM> :::4i:$; IS HlSP^ WIA AM> LU5I TANIA N r \ r<; K W-^ ilj^ X^ '-rf^^' ^ lO ^ r^^^^^S r\ ^>^ < -^ IO YEARS or A6L Fig. 23 — Comparing the expectation of life of the population of the Roman provinces Hispania and Lusitania with that of present day Americans. Plotted from Macdonell'B and Glover's data. of life of females was poorer at practically all ages of life than that of the males which exactly reverses the modern state of affairs. Macdonell believes this difference to be real and to indicate that there were special influences adversely affecting the health of females in the Roman Empire, wliich no longer operate in the modern world. Up to something like age 25 the expectation of life of dwellers in the city of Rome was extremely bad, w^orse than in the Romano-Eg}"ptian population which Pearson studied, or in the populations of other parts of the Roman Empire as we shall see in the following diagram. Macdonell thinks 92 BIOLOGY OF DEATH that this difference is real and due to circumstances pecu- liar to Rome. The general features of the diagram for the popu- lation of Hispania and Lusitania (Figure 23) are similar to those that we have seen, with the difference that the expectation of life up to age 20 or 25 is not as bad as in the city of Rome itself. Again the females show a lower expectation practically throughout life than do the males. -J b 60 65 50 A5 35 30 25 20 15 10 5 o Pi 1 ■ UN JED 5TAT ts N. s X ^-?X, - ->> ^-^ ^x N \ Ar P/CA ^ X ^- ^ ^ > N, r>s tkL. "•> ^ a^ S^ »*v S rs f^ h e^»&^ ■ > ^^ Y "% ^ ■ — ■ O 5 lO 15 20 25 30 35 40 45 60 65 60 65 70 16 60 C6 90 95 lOO YEARS or AGE FiQ. 24 — Comparing the expectation of life of the population of the Roman provinces in Africa with that of present day Americans. Plotted from Macdonell's and Glover's data. The lines cross the modern American lines at about age 60 and from that point on these colonial Romans appar- ently had a better expectation of life than the modern American has. The Romano-African population diagram appears to start at nearly the same point at birth as does the modern American, and in general the differences up to age 35 are not substantially more marked from modern condi- tions than they are in the seventeenth century Breslau table. The striking thing, however, is that at about age THE CHANCES OF DEATH 93 40 the lines cross, and from then on the expectation of life was definitely superior in the early years of the Christian era to what it is now. It should be said that the curious zigzagging of the Knes in all of these Roman tables of Macdonell is due to the tendency, which ancient Romans apparently had in common with present day American negroes, towards heavy grouping on the even multiples of 5 in the state- ment of their ages. Summarizing the whole matter we see that during a period of approximately 2,000 years man's expectation of life at birth and subsequent early ages has apparently been steadily improving, while at the same time his expec- tation of life at advanced ages has been steadily worsening. Thef ormerphenomenon may probably be attributed essen- tially to ever increasing knowledge of how best to cope with the lethal forces of nature.* Progressively better sanitation, in the broadest sense, do^\m through the centur- ies has saved for a time the lives of ever more and more babies and young people who formerly could not with- stand the unfavorable conditions they met, and died in consequence rather promptly. But just because this pro- cess tends to preserve the weaklings, who were speedily eliminated under the rigorous action of unmitigated nat- * No absolute reliance can, of course, be put upon Macdonell's or Pearson's curves. Besides laborintj under the serious actuarial difficulty of being expectations calculated from a knowledge of deaths alone, the randomness of the sampling, even on that basis, is extremely doubtful. The only real evidence that these Roman curves represent a rough pic- ture of the truth as to expectation of life in those days, arises from the consideration that they show a difference from present-day expectations which is of the same kind as that which is found between populations of one and two centuries ago and the present, and of a greater aiywunt, as would be expected from the longer time interval, and from what we know has occurred in the material development of civilization in the meantime. 94 BIOLOGY OF DEATH ural selection, there appear now in the higher age groups of the population many weaker individuals than formerly ever got there. Consequently the average expectation of life at ages beyond say 60 to 70 is not nearly so good now as it was under the more rigorous regime of ancient times. Then, any individual who attained age 70 was the surviving resultant of a bitterly destructive process of selection. To run successfully the gauntlet of early and middle life, he necessarily had to have an extraor- dinarily vigorous and resistant constitution. Having come through successfully to 70 years of age it is no mat- ter of wonder that his prospects were for a longer old age than his descendants of the same age to-day can look forward to. Biologically, these expectation of life curves give us the first introduction to a principle which we shall find as we go on to be of the very foremost impor- tance in fixing the span of human longevity, namely that inherited constitution fund anient ally and primarily de- termines how long an individual will live, ANALYSIS OF THE LIFE TABLE I shall not develop tliis point further now, but instead will turn back to consider briefly certain features of the dx line of a life table. Figure 18 shows that this line, which gives the number of deaths occurring at each age, has the form of a ver^^ much stretched letter S resting on its back. Some years ago, Pearson undertook the analysis of this complex curve, and drew certain inter- esting conclusions as to the fundamental biological causes lying behind its curious sinuosity. His results are shown in Figure 25. He regarded the dx line of the life table as a compound curve, and by suitable mathematical analysis broke it up THE CHANCES OF DEATH 95 into live component frequency curves. The data which he used were furnished by the d, line of Ogle's life table, based on the experience of 1871 to 1880 in England. This line gives the deaths per annum of one thousand persons born in the same year. The first component which he sepa- rated was the old age mortality. This is shown by the dotted curve having its modal point between 70 and 75 years, at the point lettered Oi on the base of the diagram. PEARSON'S GRADUATION OF d. 1 1 -- , ii 1 1 I r 1. ^r^ ANCr ^^ 3B \ :niLD ■HOCC L-:^ '-f ^ ^ A...«B! ^^ .-^ :>*^ Old \ \\^ ^vgyyTH^^,., — ' >^^ ^ .--- ^ <^ ---■■ \ O 2 A ; x5« ^^&s i00-' ? CnOC;'OCnoaiOCTpcnpc;iOOiOOiPCn«-'5 tOcOOOOO-^l'»~ICT>C5 0iCn'*»i*'COCON3tOi-ii_.Ot*»2 > o OD 00 b 00 •>J OJ C5 •;*• CO w *- OOi—OSlCi-'COOOCnCOKS'-' ►-OJ q. o e •a tooM>*»-^tOi*>-to>-'>— 04kOO*.cocoo>;cnO(X i—o-XJtccoH- ^ciH-cocriKjoi^^-^oo-j^o^ a 00 bo CO ^ en en CO to ^- ^- COOOp-';OCn^OO>»».tOi-'»— "Cn o tOOOCOtOrf>.t0^^tO'vlOCOOC5Cn>*».4^>;».OiO>— 05C0C04^i-'-v|i— ^rf-.H-1-i.-.tCOOtOCOOCnCOOCO C5 ^ >*>. 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CO to )-' ^- i-i % o •1 o c •o < tOCJ!OOOi—OOCnCOtO»-H-0000000000 ^H-1— io^oO'>f>>coo»co;oencncototocc>*«-'— OS b to to >- ^ O o CT>005CO^entOi-'>-'00000000000«0 ent-'Cococooxoooo*j>*».coco»oto^oo>«>.^ en 00 p 1 1 1 ibobbbbbbbbbbbbbibb »-tOK3MtOtOMi->-OOCCOOp — ' III o^i*>.co*.m'o ^ o c 1 o ■o 1 •-'OOOO'-'Oi-'OOOOOOOOOCCO 00t0CnO5£)C00O^^'^Cni*».C0t0"OOOO ' ^ ^ OC 00 O O Cn Or 00 b Cn CD Cn to ►"• t-i pptop>-'p>*^_cotototo'-'>-'>-'»-*»-' H-^ O0'-'"x>en>*»'0»-'eni-'bbobobbcnbbbcoen COC;tOrf»i-'4i.4^0tOCOCD-vlCien^«0^0>*»'>.cototoioto>-'Co>— OJ i—tocnrf^i— ^coenocococooooce;i>*'too*>toeo o JO •*«■ CO to I— 1— ►- i-'i-'CoCTii-«-jencotoi-'i-«>-' i-'to oco^ootoenH-oienoorf'.t-'cooooienJktococnrf* q- > i-'00>-'tOi-*>t*.OCienCn05'»JO-ao>— Cn'viOCO OOtOi-'4k4».Ott^^Oi^*'i-'enO"^"vI4kC>—tOOO b CO CO to >— ^ — ' OJOtOCnOOii^.tOtOi-'"-' 1—*. ooptocnop>«>.pp>A-—'Oo-qppcnco»ocococo b-^^bobbr'iocobbbb-^i">J>-'tob'oo*.bc*. 0iC0p*.-JOt0«O»K5C0C0C0^«C»0t0O«0«0*>C0 o ^ <5 -H <^ ^v a *^ r^ «> 3- H c^ o ^■*M ec s » e-. ?( ^ OS L^^ u '~*» tQ ^ ri ^ ■^ >- ^■*- o 1^ o H •< o r*. v* 5-^ o 116 BIOLOGY OF DEATH and 143 female. This is the only year of life in which the total force of mortality is heavier among females than males. From that time on to the end of the span of life, tOOOr Fig. 27. — Diagram showing the specific death rate at each age for deaths from all causes taken together. the female curve lies, by greater or less amounts, below the male curve. After the heavy mortality of early infancy, the curve drops in almost a straight line to the THE CAUSES OF DEATH 117 age period of 10-15, where it reaches its lowest point, and only approximately 2-i/^ persons out of a thousand ex- posed to risk die. The specific mortality curve then be- gins to rise, and continues to do so at an approximately constant and rapid rate for ten years — that is to the age period 20-25. From then on to the age period 50-55 it rises at a slower but constant rate. This is the period of middle life, and here the female curve drops farther below the male curve than at any other place in the span of life. After the age period 50-55 with the on-coming of old age, both male and female curves begin again to rise more rapidly. They continue this rise, at a practically constant rate of increase, to the end of life, which is here taken as falling in the age period 95-100. In this last class the rate has become very high. Out of 1,000 per- sons Living at the ages of 95 and 100, and therefore ex- posed to risk of death within that period, 494 males and 473 females die, taking an average for the whole five- year period. Of course, before the completion of the period, practically all of the thousand mil have passed away. The important things to note about this curve are these: First, the highest specific forces of mortality oc- cur at the extreme ends of life, and are higher at the final end than at the beginning. In the second place, there is a sharp and steady drop, in almost a straight line, from the high specific force of mortality in infancy to the low point at about the time of puberty. From then on to the end of the span of life, the force of mortal- ity becomes greater every year at a nearly constant rate of increase, with only such slight deviations from this constancy of rate as have already been pointed out. Turning next to the mortality of our first biological ^ 118 BIOLOGY OF DEATH group — namely deaths caused by breakdoA\Ti of the cir- culatory system, blood and blood-forming organs — we note in Figure 28 a marked difference in the form of the lOO ^'^' O ^ 10 15 ZO Z5 30 35 40 45 30 35 60 65 70 75 80 85 90 95 tOO AGE. Fig. 28. — Diagram showing the specific death rate at each age from breakdown of the circulatory system, blood and blood-forming organs (Group I). curve from what we have seen for the case of all causes of death. In the first place, the specific force of mortal- ity of this group of causes is relatively low in infancy and THE CAUSES OF DEATH 119 cliildhood. Out of a thousand infants of each sex exposed to risk, only 7 males and 5 females die from breakdo^v^l of this group of organs during the first year of life. The trough of the curve associated with the mortality r)f childhood and youth is very much less pointed than in the case of ''all causes." It is a smootldy rounded, rather than a sharply pointed depression. It is also noteworthy that between approximately the ages of 5 and 35 the specific force of mortality from diseases of the circulatory system and related organs is higher for females than it is for males. This condition of affairs is probably connected with the graver physiological changes and readjustments called forth by puberty in the female than accompany the same vital crisis in the male. From early adult life, say age 25-30 on, the specific death rate from diseases of the circulatory system and related organs increases at an almost absolutely constant rate until age 85 is reached. After that, the rate of increase slows down somewhat. Of those reaching the ages 95-100, be- tween 70 and 80 out of each thousand living die from breakdown of this group of organs. The specific mortality curve for deaths from break- down of the respiratory system, as sho\\Ti in Figure 29, presents a number of points of peculiar interest. In the first place we note that this organ system is much more liable to breakdo^vn than is the circulatory system during all the earlier years of life up to about age 60-65. The decline in the curve from the liigh point of infancy to the low point of the period about puberty is more sharp and sudden than that of the circulatory system curve. Again, however, just as in the former case, we note that tlie specific force of mortality from breakdown of this organ system impinges more heavily upon females than upon 120 BIOLOGY OF DEATH males in the years from 5-20. This difference is prob- ably connected, as before, with the greater physiological disturbance of puberty in the female than in the male. lOO I ^s ii 5 f § CO O.OI O S lO 15 ZO £S 30 35 40 4-5 £0 S5 e>0 C5 70 75 60 65 90 95 lOO AGE Fig. 29. — Diagram showing the specific death rate at each age from breakdown of the respiratory system (Group II). The lowest point of the respiratory curve falls in the age group 10-15. Between the ages 25-70 there is a very striking difference in the two sexes in respect of specific THE CAUSES OF DEATH 121 mortality from breakdo^vn of the respiratory system. The male curve rises in nearly a straight line, while the female curve lies far below it, and actually show\s a point of inflection at about age 45, becoming for a slK)rt period convex to the base. The explanation for the great sep- aration of the two curves in this period is probably fun- damentally occupational. From the nature of their activity males, during this period of life, are probably subject to a greater risk of breakdo^vn of the respiratory system than are the more protected female lives. From age 70 on, both curves ascend with increased rapidity, the female curve rising above the male, presumably in compensation for the marked dip which it exhibits in mid- dle life. It is, of course, well known that respiratory mortality bears heavily upon the aged. The next group which we shall consider has to do with deaths from breakdown of the primar^^ and second- ary sex organs. This cause group furnishes an ex- tremely interesting pair of curves shown in Figure 30. Before discussing in detail their form, a word of explan- ation as to their makeup should be given. This may best be done by exhibiting and discussing for a moment the causes of death which are included in this group. Table 10 shows the data. In this rubric are included *' Premature birth" and ** Injuries at birth." The question at once arises, why should these two items, *^ Premature birth" and ''Injuries at birth" be included with the primary and secondary sex organs, since it is obvious enough that the infants whose deaths are recorded under these heads in the vast major- ity of cases, if not all, have notliing whatever the matter with either their primaiy or secondary organs? The answer is, in general terms, that on any proper biological 122 BIOLOGY OF DEATH basis, death coming under either of these two categories is not properly chargeable, organically, against the infant at No. 151* 42 137 152* 43 37 126 132 129 134 130 136 140 131 135 125 38 128 127 133 139 TABLE 10 Primary and secondary sex organs " Cause of Death" as per International Classification Premature birth Cancer of the female genital organs Puerperal septicemia Injuries at birth Cancer of the breast Syphilis Diseases of the prostate Salpingitis and other diseases of 9 genital organs Uterine tumor (non-cancerous) . . . Accidents of pregnancy Other diseases of the uterus Other accidents of labor Following childbirth Cysts and other tumors of ovary . . Puerperal hemorrhage Diseases of the urethra, urinary abscesses, etc Gonococcus infection Uterine hemorrhage (non-puerpe- ral) Non-venereal diseases of cT genital organs Non-puerperal diseases of breast (except cancer) Puerperal phlegmasia, etc Totals Registration Area, U. S. A. 1906-10 35.7 10.8 6.8 6.6 6.5 5.4 3.4 2.2 1.8 1.7 1.6 1.3 1.1 1.0 1.0 0.4 0.3 0.2 0.1 0.1 0.1 88.1 1901-05 30.8 10.0 6.3 5.0 5.6 4.1 2.6 2.1 1.8 1.7 1.7 0.9 1.5 1.3 1.0 0.4 0.1 0.3 0.1 0.1 England and Wales 1914 46.9 12.9 3.7 2.8 10.4 5.8 4.2 0.5 0.8 1.1 0.4 1.1 0.1 0.8 1.3 1.2 0.2 0.2 0.1 0.9 77.4 95.4 Sao Paulo 1917 66.8 6.5 6.5 2.1 1.5 15.0 0.7 0.2 0.2 0.4 0.7 0.2 1.7 0.7 103.2 * In part. all, but should be charged, on such a basis, against the mother. To go further into detail, it is apparent that when a premature birth occurs it is because the reproductive THE CAUSES OF DEATPI 123 system of the mother, for some reason or other, did not rise to the demands of the situation of carrying the fa^tus to term. Premature birth, in short, results from a fail- ure or breakdown in some particular of the maternal reproductive system. This failure may be caused in various ways, which do not here concern us. The essential feature from our present viewpoint is that the reproduc- tive system of the mother does break down, and by so doing causes the death of the infant, and that death is recorded statistically under this title ^^ Premature birth. '^ The death organically is chargeable to the mother. A considerable number of cases of premature birth are unquestionably due to placental defects and the pla- centa is a structure of foetal origin, so such deaths could not be properly charged to the mother. On the other hand, however, they would still stay in the same table be- cause the placenta may fairly be regarded as an organ intimately concerned in reproduction. The same reasoning which applies to premature births, mutatis ynutandiSj applies to the item ^^ Injuries at birth." An infant death recorded under this head means that some part of the reproductive mechanism of the mother, either structural or functional, failed of normal per- formance in the time of stress. Usually *^ injury at birth" means a contracted or malformed pelvis of the mother. But in any case the death is purely external and accidental from the standpoint of the infant. It is organ- ically chargeable to a defect of the sex organs of the mother. The female pelvis, in respect of its conforma- tion, is a secondary sex character. The immediate reason for including syphilis and gonococcus infection here is obvious, but, particularly in relation to syphilis, the point needs further discussion. 124 BIOLOGY OF DEATH As a cause of actual death, syphilis frequently acts through the central nervous system, and the question may fairly be raised why, in view of this fact, syphilis is not tabled there. The point well illustrates one of the fun- damental difficulties in any organological classification of disease. In the case of syphilis, however, the difficulty in practice is not nearly so great as it is in theory. As a matter of fact, most of the deaths from the effect of syphilitic infection on the nervous system are recorded in vital statistics by reporting physicians and vital statis- ticians as diseases of the nervous system. For example, it is perfectly certain that most of the deaths recorded as due to ** locomotor ataxia '^ are fundamentally syphil- itic in origin. The rate of 5.4 for the Registration Area of the United States in 1906-10 for deaths due to syphilis is far lower, as any clinician knows, than the number of deaths really attributable to syphilitic infection. These other deaths, due to syphilis, and not reported under that title, are reported under the organ which primarily breaks down and causes death, as, for example, the brain, and will in the present system of classification be included under the nervous system. After careful consideration, it has seemed as fair as anything which could be done to put the residue of deaths specifically reported as due to syphilis under Primary and Secondary Sex Organs. The rate, in any event, is so smaU that whatever shift was made could not sensibly affect the general results to which we shall presently come. Turning now to the consideration of Figure 30, which gives the curves of specific mortality from breakdown of the reproductive organs, we note at once the high specific death rate of infants under one, recorded by the female line. This rate is over 40 per thousand exposed to risk. THE CAUSES OF DEATH 125 o It includes, of course, both male and female infants, dy- ing from congenital debility, premature birth and injuries at birth, because, according to the reasoning just exphiined. lOO X CO I CO 10 01 01 PPIMARY AND SECONDARY SEX ORGANS FiQ. 30. — Diagram showing specific death rates at each acre from breakdown of the primary and secondary sex organs (Group III). these deaths are organically chargeable to breakdo^^^l or failure to function properly of the reproductive organs of the mother. These deaths, therefore, go into the 126 BIOLOGY OF DEATH female group. By the fifth year of life, the specific rates of mortality chargeable to reproductive organs have dropped in both sexes practically to zero, amounting to less than 0.01 per thousand exposed to risk. At about the time of puberty the female curve begins to rise and goes up very steeply. By age 30 it has reached a value of 1 per thousand exposed to risk. From that point the force of this specific mortality rises slowly, but at a practically constant rate, to extreme old age. The male curve is in striking contrast to the female. From about age 20 it rises steadily, at an almost constant rate of increase, but a much slower one than the female, until the end of the life span. It crosses the female curve — in- dicating a higher specific rate of mortality from break- down of the reproductive organs in men than in women — for the first time at about age 78. This is, of course, the time of life when disturbed functioning of the prostate gland in the male begins to take a relatively hea\"y toll. Figure 31 shows specific rates of mortality from breakdoAvn of the kidneys and related excretory organs. Death from these causes is relatively infrequent in in- fancy and early childhood. The low point is reached, as in so many of the other cases, at about the time of puberty. From then on practically to the end of the span of life the specific force of mortality from excretory failure increases at an almost constant rate. During the reproductive period, from about 15 to 45 years of age, specific rates of mortality from these causes are higher in the female than in the male. After that point the male curve is higher. The relatively heavy specific mortality of the female in early life is undoubtedly due to the hea\^ strain put upon her excretory organs by child-bearing. The specific force of mortality from breakdo^vn of THE CAUSES OF DEATH 127 the skeletal and muscular systems, shown in Fitrure 32, presents an interesting pair of curves. Throughout the span of life there is practically no difference between lOO OOl Fia. 31. — Diagram showing specific death rates at each age from breakdown of the kidne>'B and related excretory organs (Group IV). the female and male in the incidence of this mortality, the curves ^vdnding in and out about each otlier. The striking characteristics of the curve are: first, that the specific forces of mortality are nbsolutoly low for those 128 BIOLOGY OF DEATH organ systems; and second, that the minimum point is reached not, as in most of the other cases, around the time of puberty, but at a much later period — namely in the too O -5 10 15 ZO Z-5 3Q 35 40 45 50 55 60 65 10 15 60 Q5 90 35 lOO AGE. Fig. 32. — Diagram showing specific death rates at each age from breakdown of the skeletal and muscular systems (Group V). late twenties. The whole curve shows a very gradual change in the rates. The next diagram, Figure 33, shows one of the most THE CAUSES OF DEATH 129 significant organ groups in the force of its specific mor- tality. Breakdo^vn and failure to function properly of the primary organs of metabolism — the organs which 100 5 Si f § OOi Fig. 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 — occur with relatively hea\^ frequency at all periods of life. These curves are among the few which show au 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 \ OOi Fia. 34. — Diagram showing the specific death rates at each age from breakdown of the nervous sj'stem and sense organs (Group VII). any portion of life. During early adult life the female cur\^e 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, wliich 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 breakdowTi 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 toAvards the end of middle life. Then the specific rates get fairly large. The low point in tliis 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 breakdo^^^l 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 lOO Fig. 35. — Diagram showing the specific death rates at each age chargeable against the skin (Group VIII). 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 sho^v^l in Figure 3G, lOO 10 3y 2-§ ENDOCRINAL 3VSTEA1 OOl Fia. 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 i.0O0rz FiQ. 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, we have the 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, a])out 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 sllo^^^l 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 anv other onran svstem 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 Age Group FEMALES Per cent, of all biologically classifiable deaths due to breakdown of specified organ system Organ system concerned in largest proportion of fatalities Organ system concerned in largest proportion of fatalities Per cent, of all biologically classifiable deaths due to breakdown of specified organ sj'stem 68.8 Alimentary tract 0— 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 sucli matters as ventilation of buildings, etc., and the putting of such a personal hygiene into general use through education, would pay about as large di\adends as could be hoped for from any investment in public health secu- rities. I am aware that much has alreadv Ix^eii 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 f ollo^\ang 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. It, makes no difference to the validity or significance of the discussion 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 mth 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 130 step further back and combine them under the headings of the primary germ layers from wliicli tlie several organs developed embryologically. To do tliis 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) Locality Death rate per 100,000 due to functional breakdown of organs embryologically developing from Ecto- derm Per cent. MeBO- derm Per cent. Endo- derm Per cent. United States Registration Area, 1906-10 191.1 210.6 177.1 134.9 14.3 15.0 14.4 8.4 425.2 407.1 374.0 468.0 31.8 29.0 30.3 29.0 719.6 786.2 681.5 1009.9 53.9 United States Registration Area, 1901-05 56.0 England and Wales, 1914. . . Sao Paulo, 1917 55.3 62.6 TABLE 13 Showing the relative influence of the primary germ layers in human mortality (Items 64 and 65 charged to mesoderm) Locality Death rate per 100,000 due to functional breakdown of organs embryologically developing from Ecto- derm Per cent. Meso- derm Per cent. Endo- derm Per cent. United States Registration Area, 1906-10 116.9 137.3 107.9 101.3 8.7 9.8 6.7 6.3 499.4 480.4 443.2 501.6 37.4 34.2 36.0 31.1 719.6 786.2 681.5 1009.9 53.9 United States Registration Area, 1901-05 56 England and Wales, 1914. . . Sao Paulo, 1917 55.3 62.6 cases still unsettled, questions of embryology. Further- more, the original statistical rubrics under whicli 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 53.5 53.9 US. REGlSTR/iT/ON AREA 1906 'iO ENGLAND and VJALES 191'^ ea.e 6^.6 SAO PAULO J917 ^ END0D5RM MESODERM ECTODERM Fig. 38. — Diagram showing the percentages of biologically classifiable human mortality resulting from breakdown of organs developing from the different germ layers. Upper bar of pair gives upper limit of mortaUty chargeable to ectoderm: lower bar gives lower limit of mortaUty chargeable to ectoderm. making up the final tables. For these details one must refer to the original papers. Tables 12 and 13, and Figure 38, give the results for the crude mortality of the U. S. Eegistration Area, Eng- land and Wales, and Sao Paulo, Brazil. EMBRYOLOGY AND HUMAN MORTALITY 141 The figures show that in man, the hi^^hest product of organic evolution, about 57 per cent, of all the biolo^-ically classifiable deaths result from a breakdown and faihire further to function of organs arising from tlie endoderm in their embryological development, while but from 8 per cent, to 13 per cent, can be regarded as a result of breakdown of organ systems arising from the ectoderm. The remaining 30 to 35 per cent, of the mortality results from failure of mesodermic organs. The two values stated for ectoderm and mesoderm, shown by the two bars in the diagram, differ by virtue of the fact that two important causes of death, cerebral hemorrhage and apoplexy, and softening of the brain, are put in the one case with the ectoderm and in the other case with the mesoderm. The pathological arguments for the one disposition as against the other of these two diseases are interesting, but lack of space prevents their exposition here. I have chosen rather to present the facts in both ways. Taking a general view of comparative anatomy and embryology it is evident that in the evolutionary history through which man and the higher vertebrates have passed it is the ectoderm which has been most widely differ- entiated from its primitive condition, to the validity of which statement the central nervous system furnishes the most potent evidence. The endoderm has been least pro- gressively changed structurally and functionally in the process of evolution, while the mesoderm occupies, on the whole, an intermediate position in this respect. Degree of differentiation of organs in evolution im- plies degree of adaptation to environment. From the pre- sent point of view we see that the germ layer, the endo- derm, which has evolved or become differentiated least in 142 BIOLOGY OF DEATH the process of evolution is least able to meet successfully the vicissitudes of the environment. The ectoderm has changed most in the course of evolution. Of this the cen- tral nervous system of man is the best proof. There have also been formed in the process of differentiation, protective mechanisms, the skull and vertebral column, which very well keep the delicate and highly organized central nervous system away from direct contact with the environment. The skin also exliibits many differen- tiations of a highly adaptive nature to resist environmen- tal difficulties. It is then not surprising that the organ systems developed from the ectoderm break down and lead to death less frequently than any other. The fig- ures make it clear that man's greatest enemy is his own endoderm. Evolutionally speaking, it is a very old- fashioned and out-of-date ancestral relic, which causes him an infinity of trouble. Practically all public health ac- tivities are directed towards overcoming the difficulties which arise because man carries about this antediluvian sort of endoderm. We endeavor to modifv the environ- ment, and soften its asperities down to the point where our own inefficient endodermal mechanism can cope with them, by such methods as preventing bacterial contam- ination of water, food and the like, warming the air we breathe, etc. But our ectoderm requires no such exten- sive amelioration of the environment. There are at most only a very few, if any, germs which can gain entrance to the body through the normal, healthy unbroken skin. We do, to be sure, wear clothes. But it is at least a debat- able question whether, upon many parts of the earth's surface, we should not be better off without them from the point of view of health. These data indicate further in another manner how EMBRYOLOGY AND HUMAN MORTALITY 1 13 important are the rundameutal em])ry()locri(.ai factors in determiiiiii«^- the mortality of man. (Jf the tliree hmal- ities compared, Enjj;land and tlie United States may he fairly regarded as much more advanced in matter's of public health and sanitation than Sao Paulo. This fact is reflected with perfect precision and justice in the re- lative proportion of the death rates from endoderm and ectoderm. In the United States and England about f).') per cent, of the classifiable deaths are chargea])Ie to endo- derm and about 9 to 14.5 per cent, to ectoderm. In Sao Paulo 62.6 per cent, fall with the endoderm, and but 6.3 to 8.4 per cent, with the ectoderm. Since public health measures can and do affect practically only the death rate chargeable to endoderm, this result, wliich is actually obtained, is precisely that which would be expected. A question which naturally occurs is as to what the age distribution of breakdo^vn of ectodermic, mesoder- mic, or endodermic organs may be. Are the endodermic organs, for example, relatively more liable to breakdown in early life, and less so later, as general observation would lead one to conclude? To answer this and similar questions which come to mind it is necessary to distribute the specific rates of Table 9 upon an embryological basis. In Figure 39 the result of doing this is shown for males. We note that prior to age 60 the curve for the breakdow^n of organs of endodermic origin lies at the top of the diagram; next below it comes the curve for the/ breakdo^vn of organs of mesodermic 'origin; and finally at the bottom the curve for the breakdown of or- gans of ectodermic origin. All three of the curves have in general the form of a specific death rate curve. The rates for all three germ layers are relatively high in in- 144 BIOLOGY OF DEATH fancy and drop at a practically constant rate to a low point in early youth. In infancy the heaviest mortality in males is due to the breakdown of organs of endodermic 1000 rz 100 5 JO 13 20 25 30 35 AO ^5 50 55 60 65 70 75 30 35 SO 95 lOO AGE Fig. 39. — Showing specific death rates in males according to the germ layer from which the organs developed. origin. This part of the death rate accounts for some- thing like 10 times as many deaths as either mesoderm or ectoderm at this period of life. From about age 12 on in EMBRYOLOGY AND HUMAN MORTALITY 145 the case of organs of ectodermic origin, and from about age 22 on in cases of mesodermic origin, the death rate curves rise at a practically constant rate to extreme old age. The ectodermic and mesodermic curves during this portion of the life span are nearly parallel, diverging only slightly from each other with advancing age. The curve for the death rate resulting from breakdown of organs of endodermic origin has an entirely different course. It rises sharply for ten years after the low point in early youth, and then makes a rather sharp bend at about age 22, and passes off to the end of the life span, at a reduced rate of change. In consequence of this it crosses the mesodermic line at age 60. From that point on to the end of life deaths from breakdo^vn of organs of mesodermic origin stand first in importance. Figure 40 shows the same set of facts for the female, and at once a number of strildng differences between the conditions in the two sexes appear. In the first place, the breakdo^vn of mesodermic organs is practically of equal importance in determining the mortality of infants with the breakdowai of endodermic organs, in the case of the female. Tliis fact, of course, arises because of the heavy mortality of infancy due to failure of the female reproductive organs, a matter wliich has already been discussed. The curve for breakdown of the ectodermic organs follows substantially the same kind of course in the female as it does in the male. The mesoderm and endoderm lines cross nearly 20 years earlier in the case of females than in the males. This circumstance arises from the fact that throughout life the mesodermic organs play a relatively more important role in the determina- tion of mortalitv in the female than they do in the male. What reward in the way of useful generalization may 10 146 BIOLOGY OF DEATH be claimed from the details reviewed in this and the pre- ceding chapter? I hope that these facts will have served in some measure to complete and round out in clearer lOOOc: AGE Fig. 40. — Showiog specific death rates for females, classified in the same manner as in Fig. 39. outlines one part of the picture of the general biology of death. It has been shown in what has preceded that nat- ural death is not a necessarv or inherent attribute or EMBRYOLOGY AND HUMAN MORTALITY 147 consequence of life. Many cells are potentially immor- tal and the potentiality is actually realized if appropriate conditions are provided. Protozoa are immortal, (ierm cells are immortal. Various somatic cells, and even tis- sues have been proved to be potentially immortal by demonstrating in a variety of ways that under appro- priate conditions they continue to live indefinitely. This is the lesson taught us on the one hand by successive transplantations of tumor cells, which are only modified somatic cells, and on the other hand by successful cul- ture of many sorts of somatic cells in vitro. Analytical consideration of the matter shows very clearly that the somata of multicellular organisms die because of the differentiations and specializations of structure and function which they exhibit in their make-up. Certain cells are differentiated to carry on certain specialized functions. In this specialization they forego their power of independent and indefinitely con- tinued existence. The cells lining the lungs, for example, must depend in the body upon the unfailing normal ac- tivity of the cells of the alimentary tract and the blood in order that they, the epithelial cells of the hmgs, may get proper nutrition. If in such an interlocking and mu- tually dependent system any one part through ac<^ident or in any way whatever gets deviated from its normal functioning, the balance of the whole system is upset. If the departure of any part from its normal functional course is great enough to be beyond correction promptly through the normal regulatory powers of the organism, death of the whole ^\dll surely ensue. What I have tried to show in this and the ]n-ecoding chapter is a quantitative picture of how the different organ systems get out of balance, and wreck the whole 148 BIOLOGY OF DEATH machine. The broad orderliness and lawfulness of the whole business of human mortality is impressive. We have seen that different organ systems have well-defined times of breakdo^vn. Or, put in another way, we see that in the human organism, just as in the automobile, the serviceability of the different parts varies greatly. The heart outwears the lungs, the brain outwears both. But we have further, I believe, got an inlding of the funda- mental reason why these things are so. It is broadly speaking, because evolution is a purely mechanistic pro- cess instead of being an intelligent one. All the parts are not perfected by evolution to even an approximately equal degree. It is conceivable that an omnipotent person could have made a much better machine, as a whole, than the human body which evolution has produced, assuming, of course, that he had first learned the trick of making self-regulating and self-reproducing machines, such as living machines are. He would presumably have made an endoderm with as good resisting and wearing qualities as the mesoderm or ectoderm. Evolution by the hap- hazard process of trial and error which we call natural selection, makes each part only just good enough to get by. In the very nature of the process itself it cannot possibly do anything any more constructive than this. The workmanship of evolution, from a mechanical point of view, is extraordinarily like that of the average automobile repair man. If evolution happens to be fur- nished by variation with fine materials, as in the case of the nervous system, it has no objection to using them, but it is equally ready to use the shoddiest of endoderm provided it mil hold together just long enough to get the machine by the reproductive period. It furthermore seems to me that the results presented EMBRYOLOGY AND HUMAN MORTALITY 149 in this chapter add one more link to the already strong chain of evidence which indicates the higlily important part played by innate constitntional ])i()lo0 AOL IN DAYS Fig. 47. — Life line3 for Droaophila m elan og aster; showing the survivors at different agea out of 1000 born at the same time. of life of Drosophila quantitatively parallels in an extra- ordinary way that of man, mth onl}^ the difference that life's duration is measured with different yardsticks in the two cases. Man's yardstick is one year long, while DrosopJiila's is one day long. A fly 90 days old is just as decrepit and senile, for a fly, as a man 90 years old is in human society. This parallelism in the duration of life of Drosophila and man is well shown in Figure 47, which represents a life table for adult flies of both sexes. The survivor- ship, or Ix figures, are the ones plotted. The curves deal STUDIES ON THE DURATION OF LIFE 180 only with flies in the adult or imago stage, after the com- pletion of the larval and pupal periods. The curve is based upon 3,216 female and 2,620 male flies, large enough numbers to give reliable and smooth results. We note at once that in general the curve has the same form as the corresponding h curve from human mortality tables. The most striking difference is in the absence from the fly curves of the heavy infant mortality which characterizes the human curve. There is no specially sharp drop in the curve at the beginning of the life cycle, such as has been seen in the h curve for man in an earlier chapter in this book. This might at first be thought to be accounted for by the fact that the curve begins after the infantile life of the fly, but it must be remembered that the human I z line begins at birth, and no account is taken of the mortal- ity in utero. Really the larval and pupal stages of the fly correspond rather to the foetal life of a human being than to the infant life, so that one may perhaps fairly take the curves as covering comparable portions of the life span in the two cases and reach the conclusion that there is not in the fly an especially heavy incidence of mortality in the infant period of life, as there is in man. The explana- tion of this fact is, mthout doubt, that the fly when it emerges from the pupal stage is completely able to take care of itself. The baby is, on the contrary, in an almost totally helpless condition at the same relative age. It is further evident that at practically all ages in Drosophila the number of survivors at any given age is higher among the female than among the males. This, it will be recalled, is exactlv the state of the case in human mortality. The speed of the descent of the Drosophila curve slows off in old age, just as happens in the human life curve. The rate of descent of the curve in early middle life is somewhat more rapid with the flies than 190 BIOLOGY OF DEATH in the case of human beings, but as will presently appear there are some strains of flies which give curves almost identical in this respect with the human mortality curves. In the life curves of Figure 47, all different degrees of inherited or constitutional variation in longevity are in- cluded together. More accurate pictures of the true state of affairs will appear when we come, as we presently shall, to deal with groups of individuals more homoge- neous in respect of their hereditary constituents. Having now demonstrated that the incidence of mor- tality is in general similar in the fly Drosophila to what it is in man, with a suitable change of unit of measure, we may proceed to examine some of the evidence regarding the inheritance of duration of life in this organism. The first step in such an examination is to determine what degree of natural variation of an hereditary sort exists in a general fly population in respect of this characteristic. In order to do this it is necessary to isolate individual pairs, male and female, breed them together and see whether, between the groups of offspring so obtained, there are genetic differences in respect of duration of life which persist through an indefinite num- ber of generations. This approaches closely to the pro- cess called by geneticists the testing of pure lines. In such a process the purpose is to reduce to a minimum the genetic diversity which can possibly be exhibited in the material. In a case like the present, the whole amount of genetic variation in respect of duration of life which can appear in the offspring of a single pair of parents is only that which can arise by virtue of its prior existence in the parents themselves indi\^dually, and from the combina- tion of the germinal variation existing in the two parents one with another. We may call the offspring, through successive generations, of a single pair of parents a line STUDIES ON THE DURATION OF LIFE 191 of descent. If, when kept under identical environmental conditions, such lines exhibit widely different average durations of life, and if these differences reappear witli constancy in successive generations, it may be justly concluded that the basis of these diiTerences is heredi- tary in nature, since by hypothesis the environment of all the lines is kept the same. In consequence of the environmental equality, whatever differences do api)ear must be inherently genetic. The manner in wliich these experiments are performed may be of interest. An experiment starts by i)lacing two flies, brother and sister, selected from a stock bottle, together in a half -pint milk bottle. At the bottom of the bottle is a solidified, jelly-like mixture of agar-agar and boiled and pulped banana. On this is sown, as food, some dry yeast. A bit of folded filter paper in the bottle fur- nishes the larvae opportunity to pupate on a dry sur- face. About ten days after the pair of flies have been placed in this bottle, fully developed offspring: in tlie imago stage begin to emerge. The day before these olY- spring flies are due to appear, the original parent pair of flies are removed to another bottle precisely like the first, and the female is allowed to lay another batch of eggs over a period of about nine days. In the original bottle there will be offspring flies emerging each day, having developed from the eggs laid by tlie mother on each of the successive days during wliieli she was in the bottle. Each morning the offspring flies which have emerged during the preceding twenty-four hours are transferred to a small bottle. This has, just as the larger one, food material at the bottom and like the larger one is closed with a cotton stopper. All of the offs])ring flies in one of these small bottles are obviously of the same age, because they were born at tlie same time, 192 BIOLOGY OF DEATH using this term ''born'' to denote emergence from the pupal stage as imagines. Each following day these small bottles are inspected. Whenever a dead fly is found, it is removed and a record made in proper form of the fact that its death occurred, and its age and sex are noted. Finally, when all the flies in a given small bottle have died, that bottle is discarded, as the record of the duration 1,000 30 36 42. 4b 5A 60 66 7^ IQ eA 90 AGE. IN DAYS Fig. 48. — Life lines for different inbred lines of descent in Drosophila. of life of each individual is then complete. All the 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 Ix line of a life table, for six different lines of Drosophila, which have been bred in my laboratory. Each line represents ' STUDIES ON THE DURxVTION OF LIFE 193 the survival distribution of the olTspring 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 olfspring 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 z 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 U line drops off very slowly until age 36 days. Prom 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 h 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 Ix 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 Ix 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 ob\'ious that the mean duration of life exliibited 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 Ix curve, but the maximum degree of longevity attained is 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 o^vn 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 tliis 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. Fig-ure 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 /.," we see the mortality curve for an hereditarily long-lived pure strain of individuals. At thebottom of the diagram the'^Type 1 V Ix '' line gives the mortality curve for one of our heredita- rily short-lived strains. Individuals of Typel andTvpoIV LOOO It 13 c-^ 30 JO -4J ^ S4 to C6 e-i M • AGL IN DAVa Fia. 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 oiTspring hybrid generation is shown by the line at the top of dia- gram marked ^ ^ Fj Za;." The Fi 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 togetluM' to produce the hybrids. The result is exactly comparable to that which has for some time been known to oc^'ur in plants, from the researches particularly of Piast and others with maize. East 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 Fj h line is 51.5 ± .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 exactlv to a vear in the life of a man. When individuals of the first hybrid generation are mated together to get the second, or Fg 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 F2 /:r." 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 F2 ?;r" 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 h,'' and "Short-lived F2 Segregates L .'' It will be noted that the long-lived Fg segregates have a mortality curve which al- most exactly 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 Fo segregates, sho^\^l 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 14.6 db .6 days. Tliis, 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 showm 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 tliis 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 wliich 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 mnding up of the \dtal clock, and by the mnding 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 otiier ways tlian by nmning do^\^l. It will be worth while to consider witii 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 Ave have just been considering Drosophila it may be ^vell 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 do^vn 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 ])oint 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 w^e 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 downi 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. Metchnikoif 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 DrosopMla 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 vnih. 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 mth 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 gro^^^l 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- pliila 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 =i= .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 w^ith 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 sho^^^l in Table 23. TABLE 23 Average duration of life of Drosophila in the imago stage at 26^ C. Experimental group Mean duration of life iu days Number of (lies) Sterile (Loeb and Northrop) 28.5 31.3 33.0 32.2 70 Non-sterile, males, all genetic lines (Pearl) Non-sterile, females, all genetic lines (Pearl) Non-sterile, both sexes, all genetic lines (Pearl) 2(:)20 3210 5830 Difference in favor of non-sterile Probable error of difference about 3.7 ± 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 role 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 1 I RAYING TAX IN PARIS 1911 - )9I3 i fe € 16 9 Tine 10 2 3 5 4 IZ 14 15 18 II ARF0NDIS5LMLNTS 13 19 ZO I n ffl 17 CLAS5LS OF /^RmaSSD€MTS PARIS 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 comiection. Hersch became interested in the relation of poverty to mortality. He gathered STUDIES ON THP] DURATION OF LIFE 203 data from the 20 arrondisscmonts of tho citv of Paris in respect of the following points, amoni»; others: a. Percentage of families not paying a personal property tar. b. Death rate per 1000 from all causes. c. Stillbirths per 1000 living ])irths. 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 MORTAUTY IN PARIS 1911 ■ I9l3 6 9 16 , 7 17 6 Z iO 3 IS IZ 4 5 ,1 15 ^ l9 20 13 '^^^5^^" ARRONDlSSCMDfrS /mmSSCMCNTS Fio. 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 ])(>pnhi(i()n is well enough to do to pay this tax. Figure 51 shows the death rates from all causes t'(»r 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. Tlie 204 BIOLOGY OF DEATH poorest districts have the highest death rates, the richest districts the lo,west 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 shoAving 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 wliit 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 Elvsee 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 snch e\i- dence as that of Hersch. TABLE 24 Stillbirths in Paris (1911-13) by classes of arrondissemenU {Hersch) Classes of Arrondissementa Absolute figures Stillbirtha per 100 living births Stillbirths Living births I II III IV 1,004 1,390 7,279 3,024 12,313 19,998 82,821 30,853 8.2 7.0 8.8 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 still])irth 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 Bro\m 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 r34.i2-=.17± .07 on the basis of the Bavarian data of Groth and Ilalin. 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 Bro^\ai made of Heron's London mate- rial, showing that in that case r34.i = .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- blv 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 vears 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 altofrether different aspect from the Parisian ficrnres. Whereas the latter increase so re 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 acti\'ity per se, and not the temperature prr 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 Eubner, 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 iveight, in the whole period from their birth to their natural death. The mean value of the constant Kubner finds to be 191,600 calories, the values for different species ranging betwx^en 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. Eubner'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- pJiila 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. Luel> and Northrop 's iinal conchision is: *'The obsers^ations on the temperature coefficient for the duration of life su^^^est that this duration is determined by the ])r()dnction of a substance leading to old age and natural death, or by the destruction of a substance or substances, whicli normally prevent old age and natural death." Tlir view wliich 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 wav necessarilv or funda- mentally contradictory to that set forth in this work. Whatever the factor whicli determines specific longev- ity may be; whether a specific chemical substance, as Loeb and Northrop suggest, or more generally, as T 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 bodv; 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 tliis specific longevity factor in each particular case is determined hy 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 availal)le evi- dence wliich definitely makes Loeb's suggestion inherently more probable than mine. It does, however, seem clear that, by definitely showing the significance of tlie lieredity element in the problem, helj) 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 mth 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 eifects of the energy relations involved. In the third place, we have only the merest suggestion of quantitatively accurate loiowledge 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 in a few trades. But the re- STUDIES ON THE DURATION OF TJFE 217 suits 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 mav 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. Tliis newspaper notoriety has especially centered about the work of Voronotf and Steinach. The only experiments wliich, 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 approjiriate 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 n timo be postponed because of the internal secretion i)()ure(l into the blood by the regenerated ''puberty glands" as he calls them. The operation wliich he finds to be most effective is to ligate firmly the efferent duct of the testis, through which the sperm normally pass, close u]> to the testis itself, and before the coiled portion of the duct is reached. The result of tliis, according to Steinacirs account, is to bring about in highly senile animals a groat enlargement of all the sex organs, a return of sexual activity, 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 is to he rememhered, however, that Slonaker's rats to which nothing was done lived to an average age of 40 moyiths. STUDIES ON THE DURATION OF LIFE 219 The presumption that Stoinacli^s experinuMits have really brought al)oiit a statistically sigiiiiicant h-ngthen- ing of life is large, and the basis of ascertained fact small. After a careful examination of Steinach\s ])ril- 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 signilicant length- ening of the life span has occurred. In ojdor 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 liistologi- cal studies on the genital organs of rats, before and aft>er 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." Komeis 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 tlie 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 Eobertson 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 a marked 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 mth the food, was tried in a variety of ways. In a recent paper, Eobertson and Eay 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) MALES FEMALES Both sexes together Class of animals Average duration of life Dev. from normal Dev. P. E. Chance dev. was acciden- tal Average duration of life a Dev. 'from normal Dev. P. E. Chance dev. was acciden- tal Chance dev. was acci- dental Normal Tethelin 767 866 719 800 +99 3.00 1:22.25 +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, mav be regarded as probablj^ 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) Age Group No. of deaths of normals (Both sexes) No. of deaths of tethelin fed (Both sexes) 200-299 3 Tethelin fed: Mean age at death =839 ±20 300-399 2 , . Normal fed: Mean age at death ^=743±17 400-499 2 1 Difference 96±26 500-599 600-699 9 7 3 9 Difference = 3.7 P- ^- Diff. 700-799 15 . . 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 wliich is just significant statistically. One would expect, from the variation of random sampling alone, to get as divergent results as these about IV'i times in every 100 trials mth 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 Brosopliila 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 Avith 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, AXD TIIK POPULATION PROBLEM. SUMMARY OF RESULTS I have attempted to review some of the imi)()rtant biological and statistical contributions wliich 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 ]^artic- 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 t)f the investigations of Loeb upon artificial ])arthenogenesis and related phenomena. The essential and important 2'J3 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, etc. 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 22; of the body along the evolutionary pathway appears to be an important factor in determining tlie time wlien 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, tlie second large result is that it is the way potentially innnortal 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 indi\idual, passed on from parent to otfspring, just as is eye color or hair color, and with a relatively liigii degree of precision. Tliis 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 wliich determines the way the organism is put together — the organization of the parts. And it is when parts break down and tlie 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 ill 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 ; wliile 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 macliine. 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, pro\dded 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 Kubner, 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 likuly to yield large returns. PUBLIC HEALTH ACTIVITIES Fortunately, it is possible to get some ligkt on tlic 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 diniculty 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 kno^vn, 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 mil be good, bad or indifferent. Hence many kinds of weird acti^dties 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 tliis 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 w^ould 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, w^hether 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 mth 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 T would especially direct attention. 230 BIOLOGY OF DEATH CONTROLLABLE. CAUSES OF DEATH IfiOO r^ 100 § o § 1^ 5 ;3: 0.1 Zi^^S^^^ffSfS or rH€ LUNGS \. — . — ^^ ^^^ I I I I I I I I I I I I I I I I I 1900 01 OZ 03 04 05 Ob 07 Od 09 10 II l^ /J lA i5 16 17 Id YEAR Fig. 52. — Trend of death rates for four causes of death against which public health activities have been particularly directed. In figure 52 are given the trends of the death-rates for four diseases against wliich pnblic health and sani- tary activities have been particularly and vigorously I NATURAL DEATH, PUBLIC HEALTH 231 directed, with, as we are accustomed to say, most grati- fying results. The diseases are: 1. Tuberculosis of the lungs. 2. Typhoid fever. 3. Diphtheria and croup. 4. Dysentery. We note at once that the death-rates from these diseases have all steadily declined in tlio 19 years under review. But the rate of drop lias been sli^^litly uncfiual. Remembering that the slopes are comj)arable, 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 Ignited 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: 1. Bronchitis (acute and chronic). 2. Paralysis without specified cause. 3. Purulent infection and septicaemia. 4. Softening of the brain. Now it will be granted at once, I think, that public health and sanitation can have had, at liie 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 j)atli()l(>gical entities far beyond the present reach of the health ulUcer. Yet the 232 1,000 BIOLOGY OF DEATH NON - CONTROLLED CAUSES OF DEATH 100 o o o 0. 10 5 f § 0.1 '--"^"^Zi^w. '^/q anaf CA '^O/7/cj ^^^^'l KsyJ' ^'THour ;> ~€A/r v„.X.- ...^_ '^^^rc^^ ws or ^^ ^^■A//s/ S. I I I I I I I I 1900 01 02 03 04 05 06 07 03 09 10 II II 13 I4- 15 16 17 Id YEAR Fio. 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 showTi in Figure 52. It is of no moment NATURAL DEATH, PUBLIC HEALTH 233 1.000 100 o q: 10 d..£2^^0u^SLC ^^L/S€S "••»"••• 5 ^ ^ 0.1 ^^os. '^es IQOO 01 0^ 03 04- 05 06 07 08 09 10 II IZ 13 i-i- /J 16 I7 id YEAR FiQ. 54. — Trend of combined death rate from the four causes shown in Figure 52 as compart with the four causes shown in Figure 53. 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 dilferent 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 difiicult 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 tliis group, T 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 ^\ish 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 mil 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 w^holly, or nearly so, to changes in the practice of physicians relative to the reporting of the cause of NATURAL DEATH, PUBLIC HEALTH 235 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 exain]jle may be cited to illustrate the same general point. Suppose we compare the course of mortality from certain wull- delined 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 Kouniania Without going into detailed comi)arisons, which might be thought invidious, it is evident on the face of the case, I think, that the countries in the A group w(»re, 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 e\ddent 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 mth the natural history of disease always played 100 "yi 10 TYPHOID FLVER - -.ff^^^ ••- ♦. ••». •• '•^^OOA 1698 99 1900 01 0^ 03 04 05 06 O? 08 09 YEAR 10 II 1^ Fio. 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 role 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 237 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 mortalitv in time is an 18^ 39 000 01 03 04 05 06 YEAR 07 06 OO 10 II |^ Fia. 56. — Like figure 55, but for diphtheria and croup. extraordinarily complex biological phenomenon, in wliich many factors besides the best efforts of hoiillh officials are involved. 2. That for manv causes of death a vast lot needs to be added to our knowledge of etiolog}', in the broadest sense, before really efficient control can Ik' ho]^ed for. This knowledge can come only through scientiiic 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 Joard 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 kno\\ai, 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. *'lt is well understood, not only by scientists, but also by intel- ligent laymen, that the spread of the infection may b(; prevented by mosquito control, by protectin^^ people I'roni being bitten by mosquitoes, or by destroying the parasite in the blood of the human carrier. It has been sIkjwu, 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 Ix* reduced indefinitely. There are few diseases that pre- sent so many vulnerable points of attack and none j^er- 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- cribing the work Rose says: "Effort has been made to test the feasibility of malaria control ii» small communities by resort to such simple anti-moscjnito measure as would fall within the limits of expenditure that such communities mi},'ht well afford. The habits of the three mosquitoes — .1. (piadrimaruUitus Say. A. punctipennis Say, and A. cruzians Wiodermann — which are ropunsihle for the infection in these communities have been made the subject of constant study with a view to eliniinutiii;^ all unnecessary effort, and tluTi'by reducing coat. "Experiment at Crossett, 11)16 — The first of tlit'se 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 aljundant breeiling 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 causo of about GO per cent, of all illness through- out the region. Within the town itself the nmlaria rale was high, and was recognized by the lumber corporation and the people as a seriou* menace to health and working ellieicncy. "The initial step in the experiment was a survey of the community to determine the malaria incidence, to ascertain in the species of niosquitoeti 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 sliowu in Figure 57, as measured by a number of physicians' calls for the treatment of ma- laria in the community. The second examijle 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 ^^dth wliich this disease can be controlled. The diagram shows the results of the International Health Board's yellow fever work in Guayaquil in 1918-1920. t 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-ARKAr SSA5 Calls for Malaria 191 5 1916 1917 1918 SBO S60 sto S2o 40O 46C :^:: 420 ; L .6s 400 ._ ____JL__X 380 1 QJ ■ ! ^ 1. ; r J| - ^ — _ ; L 5 i s i ^„^ 1 1 -J^- leo 1^ 1 i b^ _ __ ___▼ L-I t Z-—1L i _is t_ Z I 1 Tli^* Mini i 1 1 1 1 III 1 n 1 iiiiiiiiiiiii i n 1 II n ni nniiiiiiiiiii «^ HH ■ ■ ■ ■ 1 [iTiinrrTiTni t^ m. " " Miii'iM 1 iiippnmmi ill .._-_..-. T lilil] 1 : ^ 1 Monthly Distribution of Calls Popula tion, 2029 '5 "^ '^/6 1^1 m TotslOalts 1^15 2500 JAN A FEB A MAKCH i APRIL ( MAY i ^5 40 C 3 ^5 39 7 2 >G 59 13 4 >0 81 12 8 )0 1(4 31 2 /9/6 '- 741 /917 - 200 /?'« - 71 JUNE 1 20 98 13 « ^jy^Z^'^S^ Reductton, iV5-i^i6 97. » JUL/ 2i AU^ 3 SEPT 5< OCT W( MOT. 3 acs. . . 1( 00 'y^ ^ 50 91 33 7 Per Capita C X) 54 22 II 30 46 14 8 50 2D a3 7 30 4 15 10 \0St: 191^ - 124 /9/7 - *3 /y/9 - -53 FiQ. 57. — Record of malaria control by anti-mosquito measures, CroMott. Ark. 1916-1918. (From Rose). 16 242 BIOLOGY OF DEATH 191 8 II 1 1 ■ UJ < - 0£ . ....... 919 920 C IE ^1" " 81 ,88 ll 1 72 ll 1 ft it _ -4 1 ) I .. 40 43 li ) — lit i u tit J m tit L 22 It ■■-■■ IHlii . 12 1 Jjl 1 -BI m 5 II Itt Mmni tlllli Oi 0' MMMT IE CO X = S >^ <-> oc -^ u. ae QL » >■ UJ . :3 i M = t .2 - 1- I- J i s i til g gf i ^ i g si G § g = 5 5 t^ o z <=» z to 5 lii a: : -J >- UJ >- C3 f 1 ^ 1^- « MONTHS 1 I -Disappearance of yellow fever from Guayaquil. Ecuador, as a result of control measures. (By permission of International Health Board). NATURAL DEATH, PUBLIC IILAL'ni 213 born, than was formerly the case. It is fiirlhcrnirire plain tliat if nothinii: liappens to tlio l»irl}i-rat(' I hero must eventually be as many persons livinic upon the hal)ital»le parts of the g-lo])c as can possibly be supported with food and the other necessities of life. Malthus, whom every one discusses but few take the trou])le to read, pointed out many years ago that the prol>Iom of ])opu- 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 otherAvdse remain alive, adds to the difficulty of the problem of population. We have just seen that tliis 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 T have recently done, these death-liirth ratios for different countries, we (inlrth ratio in general rose throughout the war ])eriod. 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 went on making a not 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 sho^vn 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, showai in Figure 4, with data from the United States and England and Wales for comparison. Prob- ably no single large city in the w^orld was so hard hit by the war as Vienna. Yet observe what has hai)pened 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 tow^ards the normal after even so disturbing an npset 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 wdiich 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. 'S50 GIZ J9I3 ' " 1914. ' i9lS I9l0 1917 l^ig i&'& '^^O WEAR Fig. 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 fig-ure indi- cates 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 IILALTII 1>17 The first thing obviously needed in any scientific approach to the problem of popnlation is a j^'oixt mathe- matical determination and expression of the law of popu- lation growth. It has been seen that the most devastating calamities make but a momentary flicker in the steady progress of the curve. Furthermore, ])()pulation j^rowth is plainly a biological matter. Tt 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 ])oj)ulations, my colleague, Dr. Lowell J. Reed, and T 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. Tliis gave a fairly good result over the period, Init was obWously ])urely 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 hj'pothesis as to the more ini])<)rtant biological factors involved, and tested the resulting equation against the facts for a variety of countries. The hypothesis was built up around the foll()^\^ng considerations : 1. Li any given land area of fixiMJ limits, as Ity political or natural boundaries, there nuist necessarily be an upper limit to the number of persons tliat 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 popuhition in a ^iven area will be, and when it wdll be attained. Furthermore, one can tell exactly when the population is growing at the maximum rate. To test the theor}% we have only to fit Fia. 60. — Showing a theoretical curve of population growth. this theoretical curve to the kno^\Tl facts of population for any country by appropriate mathematical methods. If the hypothesis fits w^ell all the known facts for a variety of countries in different stages of population growth, it may w^ell be regarded as a first approximation to a sub- stantially correct hypothesis and expressive of tlie bio- logical law according to wdiich population grows. In making this test the statistician has somewhat the same * The mathematical hypothesis here dealt with is essentially the wime as that of Verhulst, put forth in 1844. As Pearl and Keod pointc, 1899. Beetox, M. and Pearson, K. On the inheritance of the duration of life, and on the intensity of natural selection in man. liiumctrika, Vol. 1, pp. 50-89, 1901. Bell, A G. The duration of life and conditions assoi-iateil with longevity, A study of the Hyde genealogy. Washington, liUS pp. ')7, 4to ( Privately printed ) . Benedict, Harris M. Senile changes in leaves of Vitis vulpiua L. and certain other plants. Cornell Agr. Expt. Stat. Mem. 7, pp. 273- 370, 1915. Bertillon, J. Morbidity and mortality according to occupation Jnur. Roy. Stat. Soc, Vol. LV, pp. 5.39-600, 1892. BoGDANOW, E. A. Ul)er das Ziicht^'n der gewiihnlichen Fleischtliegen (Calliphora vomitaria) in sterilisierten Xahrmitteln. .In7i. /. d. get. Physiol. 1906 BoGDANOW, E. A. Uber die Abhiingigkeit dos Wachstums der Fliegen- larven von Bakt^'rien iind Fermenten und iiU'r N'ariabilitiit uiul \"»iit- bung bei den Fleischfliegen. Arch. f. Annt. u. Physiol., ( Phy$iol. Ahth.) 1908, pp. 173-199, 1908. Bulloch, W. and Greenwood, M. The problem of tulx'rculosis ccmsidered from the standpoint of disposition. Proc. Roy. Soc. Med , -May, llMl, \'ol. IV, Epidem. Sect., i)p. 147-184. 259 2G0 BIBLIOGRAPHY Burrows, M. T. The tissue culture as a physiological method. Trans. Cong. Amer. Phys. and Surg., Vol. IX, pp. 77-90, 4 plates, 1913. Carrel, A. On the permanent life of tissues outside of the organism. Joir. Exper. Med. Vol. XV, pp. 516-528, 2 plates, 1912. Carrel, A. 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INDEX Acaiiihias, 3S Accidental deutlis, lUT Activity, mctiihulic, 211-217 Agamic reproduction, 33, 35, 37, 41, 77 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, G8 Anopheles cruzians, 239 punctipennis, 239 quadrimaculatus, 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, 220 Bacteria, rOle of, in duration of lift', 43, 199-202 Bataillon, 52, 259 Bavaria, 244, 245 Bee, senility in, 28 Beeton, M., 166, 169, 171, 2.VJ Belgium, 256 Bell, A. G., 152-158, 165, 166, 225, 259 Benedict, H. N., 44, 259 Bertillon, J., 216, 259 Bibliography, 259-288 Bills of mortality, 79 Biological classificatiun of cauMs of death, 101-137 Birds, longevity of, 22, 63 Birth control, 257 injuries at, 121, 123 premature, 121, 123 Blood, 107, 108. 111. lis. 11«> Body size and longevity, 26, 68 ■weight. OS Bogdanow, K. A., 200, 259 Brain ^veight, 68 Brazil, 106 Brighfs disease, 161 Bronchitis, 231, 232 Brown, J. \V., 206, 261 Brownlee, J., 183 Budding, 37 Bulloch, W., 259 Burrows, M. T., 59-62, 260 Callithrix, 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 bioli>gical dassili- catii»n of. 104 international clas- sifuation of, 103 non-controlled, 232, 233 Cells, interstitial. 219 Cellular immortality, 51-78 269 270 INDEX 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 Dawson, M. M., 82, 260 Death, appearance of in evolution, 42 biological classification of causes 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 Diarrhoea, 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 mclanogaster, 186-202, 208-211, 214, 222, 225, 226, 253, 254 Dublin, L. I., 82, 113, 260, 261 du Xoiiy, 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 271 Duration of life of domestic fowl, G.J of pareiit*i and olT- Kpriii^', !">')- 157 rOle of bacteria in, 43, 199-202 variation in, 21, 22, 08, 80-82 Dysentery, 230, 231 East, E. M., ID."), 2.')7, 201 Ebeling, A. H., 60, 01, 74, 70, 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, 201, 268 Eudorina elegans, 31, 73 Eugenics, 227 Education Society, 257 Evolutionary progress in longevity, 87-94 Evolution of ectoderm, 141 of endodtrin, 141 of mesoderm, 141 of workmanship of, 148 Excretory organs, 107, 108, 111, 120, 127 Exercise, 212, 213 Expectation of life, defined. 82 changes in, 82-94 i-xpecttttion of life, effect of itelertion on, 94 hyjH»thptiral, 164 in ant-ient E^pt, 87-80 in ancieut Home, 90 92 ill Hihipania and Lubitania, 91- 92 i n K o til a n Africa, 92 93 Experimental study of duration of life, 180-222 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 recjuirements, 256 Forsyth, C. H., 161, 104, 261 Fowl, duration of life of, 63 France, 244, 245, 251, 252 Franco-Prussian wur, 2.'»2 Fraternal correlations, 171. 172. 175, 170 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. I). H. C, 238, 201 CJland, pituitary, 220-222 Glands, puberty. 217-219 272 INDEX Glaucoma pyriformis, 73 Glover, J. W., 80, 84, 88, 90-92, 261 Gonads, 217-219 Gonococcus 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 Guyenot, 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 Immortality, cellular, 51-78 human, 17-20 of protozoa, 30-33, 64 of somatic cells, 58-78 Industrial mortalitv, 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 m a n, 150-185 of physical characters, 174, 175 Injuries at birth, 121, 123 Insects, longevity of, 22 International classification of causes of death, 103 Health Board, 238- 240, 242 Interstitial cells, 219 Invertebrates, longevity of, 22 In vitro culture of tissues, 58-78 Italy, 235 Jamaica, 235 Jennings, H. S., 31, 33, 40, 41, 45, 71, 72, 263 Jickeli, C. F., 44, 263 Jollos, 33, 263 Jones, D. F., 261 Kassowitz, M., 44, 263 Keimhahn, 40 Kidneys, 61, 107, 108, 111, 126, 127 INDKX 273 Kopf, K. W., ll.J. JGO Korscliolt, K., 2G3 Landed Geiiliy, 1(»7. !()'.>. 17-' Lankaster, E. K., 2(>:\ Levassour, E., S2. 203 Le«;rand, M. A., 2r):} Lewis, ^L Tv., 02, 20;i Lewis, W. IL, 53, 54, 62, 263, 264 Life, aseptic, 43, 200-202 ilian^^e.s in expectation of, 82-lU curve of Hvde family, L")3 cycle of Drosophila, 187, 188 prolonp:in^, 17, 54, 218, 221 table, 70-82 analysis of, 94-101 Breslau, 83, 84, 02 Carlisle, 83, 80 U. S., 1010, 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, 220, 263, 264 Loeb, L., 59, 64, 65, 67, 224, 264 Logarithmic plottin*^, 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. \V. R., 87, 89-93, 229, 261 Malaria, 238-241 Malthus, T. K., 243 Mammals, longevity of, 22 Man, longevity of, 23-26, 80-94 Marmoset, 08 Mendelian inheritance, 194, 197, 108 Mesoderm, 138-149 Metabolic activity, 211-217 Metazoa, 31, 33, 40, 46. 71 MetchnikofT. E.. 43, 109, 200, 264 Methml of deftcent, 40-42 MicronucleUH, 72 Minot, C. 8., 27, 28, 44, 71. 264 Mitchell. P. C, 264 Mitosis, fll M.)ntg(.m«Ty, T. II., 44, 265 Morgan, T. H., 10, iHrt. 197, 265 Mortality, billh of, 79 curve, gruduntion of, 04- 101 cmbrytdogical 1>a»is of, 138-149 industrial, 216 infant, 205, 206 intliu'uce of poverty on, 2(t2-20S organ system in, 107, lOS :Mo.s«iuito, 239. 240 Most fatal organ systems, i;i6 Mouse, 68, 220-222 growth of. 69 70 .Miihlmann, M., 44, 265 Muller, J., 44 Miiller, L. R., 265 Muscular system, 107, 108, 112, 127, 128 Xascher, I., 26, 27, 265 Nerve cells, senile clianges in, 27-29 Nervous system, 107. lOS. 130. 131 Netherlands, 256 Non-controlled causes of death, 232. 233 Northrop, J. 11.. 200, 201, 209-211. 214, 215, 226, 264, 265 Nucleus, 29. 30, 44 Occupation, 216 Ogle. W.. 95 Orbits, 250 Oriran systems in mortality, 107, lOS most fatal, 136 Oxi/trichn hiftnrnDStuma, 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 Preventabilitv 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 Public 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, 139, 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, 30 Royal families, 177 Rubner, M., 213, 214, 226, 267 Saleeby, 183 Sanitation, 227, 235 S5o 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 iM)i:x 275 Seneficonee, 27-.K). 4i». 70-7H theories of. 4.*i TiO Senile clianjies in lu'ive f«'lU, "27 i'.l Senility as cause of deatli. h)'.> in plants. 44. 7 t. 7;') Septicipniiu, 231, 2:{2 Serbia, 2r)2. 253 Serum, iiithioiice on ti>sMi' cnllnrf. 76. 77 Sex or«^aiis, 107, lOS, Ul. 12112... 217-219 Sexual reproduction, M 4\ Shell. .].. 26, 27 Skeletal system, 1(»7, Kts, 112. 127. 128 Skin, 107, 108, 110. 112, 131, 132 Slonaker. J. M., 212, 213, 218. 228. 207 Slotopolski. B.. 33. 267 Snow, E. C, 179-183, 225, 267 Softening of the brain, 231. 232 Soma, 40 Somatic cells, immortality of, 58 7 S Span, 174, 175 Spiefxplltei-^. W., 87 Spiritualism, 18-20 Spleen, 61 Spon«;es, 62 Stature. 174, 175 Steinach, E., 217-219, 267 Stcnost07num, 35, 36 Stevenson, T. H. C, 206-208, 267 Still births, 205 Strongylocentrotus purpiinitiis. .■).".. 56 Summary of results, 223-227 Survivorship lines of Drosophilu. 188, 192. 195 Syphilis, 123 Table, life. 79S2 Temperature, 208-217 Tethelin. 70. 220 222 Thii)ries of deuth, 43 50 Theory of population );ruwtti. J4'.i Thyroid ^lUnxd, 01 Tissue culture in vitro, 5K 7K TranHplantation of tuinorit, 64, tt.'> Iiibenulohih. 101, 204. 20^. 230 2.'tl 238 I umor traiii-plunlution, 04, 05 Typhoid fever, 2.30, 231, 235, 230 I'nitetl States, jfrowth of, 250 2.V2, 254-257 V rusty la granfiin, 72 Van iiuren, G. ii.. 113. 260 N'ariation. ^'enetic, 190 X'enereal diseases, 123, 124 Verhulst. P. K.. 249. 267 \'erworn, M., 44. 207 \ienna, 245. 246 Voronoff, 217 Waller, A. I)., 216. 267 Walworth. K. II.. 152. 207 War, 243 Wedekind. 33. 207 Weismann, A., 20, 43. 65, 207 Whale. lon;.'evity of, 22 Wilson. H. v.. 62, 267 Wittstein. 99 Womlruir. L. L.. 30. 33. 72. 73. 267. 208 Wo(k1s. F a.. 38. 39. 2r.S Vellnw fever. 240. 242 Y<.un''. T. K.. 23 25. 208 f North Carolina State University Libraries QH559 .P4 BIOLOGY OF DEATH BEING A SERIES OF LECTURES D S02776595 Q ^■iiiij iiiiil'