In work of this kind, rigid asepsis is required to exclude the possibility of bacterial infec­tion and this was first done by Salkowski, who showed that in aseptically kept tissues like liver and muscle the amount of substances that can be extracted with hot water increases considerably. By the work of others, especially Martin Jacoby and Levene, it was established that the power of self-diges­tion is shared by all organs. Analysis of the products of the autodiges­tion of tissues shows that, e. g., the amino acids, which constitute the proteins, are produced. Dakin, Jones, and Levene demonstrated the hydrolytic products of the nucleins, in the case of the self-diges­tion of tissues.297

Again the ques­tion arises: Why do the tissues not undergo autolysis during lifetime and what protects them, and the answer is that self-diges­tion is a consequence of the lack of oxida­tions. The presence of antiferments must continue after death and cannot be the cause which prevents the self-diges­tion during life, since nothing indicates the destruc­tion of the hypothetical antidigestive enzymes through lack of oxygen. The recent work of Bradley and Morse298 and of Bradley299 has thrown some light on the problem. These authors found that proteins of the liver which are indigestible can be made digestible by the liver enzymes if an acid salt or a trace of acid is added to the mixture. A m/200 HCl solu­tion gives marked accelera­tion of the autodiges­tion of the liver. This would explain why autodiges­tion takes place after oxida­tions cease. In many if not all the cells, acids are constantly formed during lifetime, e. g., lactic acid, which through oxida­tion are turned to CO₂, and this diffuses into the blood so that the H ion concentra­tion in the cells does not rise materially. If, however, the oxida­tions cease, as is the case after death, the forma­tion of lactic acid continues, but the acid is not oxidized to CO₂ and thus removed, and as a consequence the H ion concentra­tion increases in the cells and the self-diges­tion of proteins, which the digestive enzymes contained in the cells themselves could not attack formerly, becomes possible. Acid increases the digestibility of a protein, probably by salt forma­tion. Theoretically we should not be surprised that while in the liver an increase in the C_H favours autolysis in other tissues the same result is produced by the reverse effect. We might say that the preserva­tion of a certain C_H probably at or near the point of neutrality during life prevents self-diges­tion, while the gross altera­tion of the C_H in either direc­tion after death (or after the cessa­tion of oxida­tions in the tissues) induces autolysis. Bradley indeed suggests that many of the phenomena of autolysis during lifetime, such as atrophy, necrosis, involu­tion, might be due to an increase in the C_H in the tissues.

These facts agree with the suggestion of Fermi that in the living cell the proteins cannot be attacked by the digestive enzymes but relieves us of the necessity of making the monstrous assump­tion of a “living molecule” of proteins as distinct from a “dead” molecule. The difference between life and death is not one between living and dead molecules, but more likely between the excess of synthetic over hydrolytic processes.

In the second chapter we mentioned the interesting idea of Armstrong that when a synthesis is brought about by a digestive enzyme (e. g., maltase) not the original substrate is formed (e. g., maltose) but an isomer, in this case isomaltose; and this isomer is not attacked by the enzyme maltase. We thus get a ra­tional understanding of the statement which Claude Bernard used to make but which remained at his time mysterious: la vie, c’est la créa­tion. During life, when nutritive material is abundant, through the reversible action of certain enzymes, synthetic compounds are formed from the building stones furnished by the blood. These synthetic isomers cannot be hydrolyzed by the enzymes by which they are formed and hence on account of the isomeric structure are immune against destruc­tion. It is not impossible that the increase of the concentra­tion of acid in the cells after death trans­forms the isomers into that form in which they can be digested by the enzymes contained in the cell. Another possibility is that the increase in digestibility brought about by an increase in C_H in the cell is due to the hydrating effect of acids on proteins with a subsequent increase in digestibility. Whatever the answer may be, the work done since Claude Bernard has removed that cloud of obscurity which in his days surrounded the prevalence of synthetic action in the living and of disintegra­tion in the dead tissues.

3. We have already referred to the connection between the lack of oxygen and the onset of autolysis and disintegra­tion of tissues in the body. It is of interest that there are cells in which the disintegra­tion under the influence of lack of oxygen is so rapid that it can be followed under the microscope. The writer has observed that certain cells undergo complete irreversible dissolu­tion in a very short time under the influence of lack of oxygen, e. g., the first segmenta­tion cells of the egg of a teleost fish Ctenolabrus.300

The phenomenon of rapid disintegra­tion when deprived of oxygen (or in the presence of KCN) seems to be general as Child303 has shown in extensive experi­ments. Child has used it to show that younger animals disintegrate more rapidly than older or larger ones, and he uses this fact for a theory of senescence. He connects the more rapid disintegra­tion of the young animal with a greater metabolism.304 Without wishing to doubt Child’s interesting observa­tions the writer is not quite certain whether the more rapid disintegra­tion of the younger forms is not a result of the fact that the walls of membranes in the young are softer than those of the older animals, and hence are more readily liquefied. Such a difference could be due to mere chemical constitu­tion, e. g., the increase in Ca in the membrane with the increase in age. In old age in man the deposit of Ca in the blood-vessels is a frequent occurrence.

These facts may help us to understand the nature of death and dissolu­tion of the body in higher animals. Death in these animals is due to cessa­tion of oxida­tions, but the surprising fact is that if the oxida­tions have been interrupted but a few minutes life cannot be restored even by artificial respira­tion. This suggests that the respiratory ganglia in the medulla oblongata suffer an irreparable injury or an irreversible change (comparable to that just described in the cells of Ctenolabrus) even when deprived of oxygen for only a short time. As a consequence of the irreversible injury to the medulla the respira­tions cease permanently, the heart-beat must also cease, and gradually the different tissues must undergo the dissolu­tion characteristic of death. While all the cells may be immortal they are only so in the presence of oxygen and the nutritive solu­tion which the circulating blood furnishes. With the proper supply of oxygen cut off they can no longer live.

4. It is an unques­tionable fact that each form has a quite definite dura­tion of life. Unicellular organisms are immortal; but for the higher organisms with sexual reproduc­tion the dura­tion of life is almost as characteristic as any morpho­logical peculiarity of a species. No species can exist unless the natural life of its individuals outlasts the period of sexual maturity; and unless the average dura­tion of life is long enough to allow as many offspring to be brought into the world as will compensate for loss by death. The male bee dies before it is a year old, while the queen may live several years. In a certain species of butterflies, the Psychidæ, the partheno­genetic female lays its eggs while still in the cocoon and then dies without ever leaving the cocoon. The imago of the ephemera leaves the water in the evening, copulates, lets its eggs fall into the water, and is dead the next morning. The imperfect condi­tion of their mandibles and alimentary canal makes them unfit for a long dura­tion of life. The males of the rotifers which are devoid of organs of diges­tion live but a few days.

In the Zoölogical Station at Naples in 1906, an actinian, Actinia equina, was alive after having been in captivity fifteen years, and another one, Cerianthus, had been observed for twenty-four years. Korschelt kept earthworms for as long as ten years. The fresh-water mussel may reach the age of sixty years or more and crayfish may live for over twenty years. The differences in the dura­tion of life of mammals are too well known to need discussion. If the cells and tissues are immortal, how does it happen that the dura­tion of life is so characteristic for each species?

Metchnikoff305 has recently investigated the cause of “natural” death in the butterfly of the silkworm. The butterfly in this species lacks the organs necessary for taking up food, like the male rotifer or the ephemeridæ and hence is already, by this fact, condemned to a short life. Metchnikoff observed that these butterflies could live twenty-three days, but the average dura­tion of life was 15.6 for the males and 16.6 days for the females; and that seventy-five per cent. of them contained no parasitic fauna or flora in their intestine. They lose considerably in weight during their lives, but the males still contain the fat body at the time of death. None of the changes accompanying “old age” in man are found in the tissues of these butterflies before death. Metchnikoff is inclined to believe that the animal is poisoned by some excre­tion retained in the body; namely, the urine, and that this poison also causes the symptoms of weakness which characterize the animal. He could prove the toxic character of their urine on other animals. This combined with starva­tion could sufficiently account for the short dura­tion of life. The facts of the case show that it is due to an imperfec­tion in the construc­tion of the organism such as one would expect to find more or less in each animal if one discards the idea of purposefulness and divine wisdom in nature. Only a slight, perhaps an infinitesimal, fraction, of those species which are theoretically possible and which at one time or another arise can survive. Those which are durable show all transi­tions from the grossest disharmonies to an apparent lack of such shortcomings.

5. Minot had tried to prove that the death of metazoa is due to the greater differentia­tion and specializa­tion of their tissues. Admitting the immortality of the unicellular organisms he argues that death is the price metazoa pay for the higher differentia­tion of their cells. This is of course purely metaphorical, but we may put it into a form in which it is capable of discussion in physico­chemical terms, by assuming that death is a necessary stage in the development of a species. We are inclined, however, to follow Metchnikoff and suspect some poison accidentally or unavoidably formed in the body or some structural shortcoming as the cause of “natural” death.

An unusually favourable object for the study of natural death is the animal egg. The egg of the starfish Asterias forbesii when taken out of the body is usually immature, but in the spawning season it ripens in sea water. The writer306 observed that eggs which ripen disintegrate very rapidly when not fertilized. This disintegra­tion may be due to a process of autolysis, which sets in only after the egg has extruded the two polar bodies. The writer found that by preventing the matura­tion of the egg either by withdrawing the oxygen or by replacing the alkaline sea water by a neutral solu­tion or by exposing the eggs for some time to acidulated sea water, the disintegra­tion could also be prevented.

Further experi­ments showed that even in the mature egg rapid disintegra­tion could be prevented by lack of oxygen, and similar results were obtained by Mathews. When the egg is fertilized it does not disintegrate in the presence of oxygen but it gradually dies in the absence of oxygen. One is almost tempted to say that while the fertilized egg is a strict aërobe the mature unfertilized egg is an anaërobe. This latter statement, however, becomes doubtful since the presence of oxygen may help the disintegra­tion only indirectly by allowing certain changes to go on in the egg. The important points for us are that dura­tion of life in the mature unfertilized egg is comparatively short and that the entrance of a spermato­zoön or the process of artificial parthenogenesis saves the life of the egg. Loeb and Lewis found that the life of the unfertilized sea-urchin egg (which is usually mature when removed from the ovaries) can also be prolonged when its oxida­tions are suppressed. The decay of the unfertilized egg seems to be due to the fact that those altera­tions in the cortical layer which underlie the membrane forma­tion and which are responsible for the starting of development gradually take place. In such a condi­tion the egg will die quickly unless deprived of oxygen. This view is supported by the observa­tion of Wasteneys that unfertilized eggs of Arbacia show an increased rate of oxida­tions when allowed to remain for some time in sea water; we have seen in Chapter V that such an increase also accompanies artificial membrane forma­tion.

6. If the limited dura­tion of life of an organism is determined by one or more definite harmful chemical processes, we should expect to find a temperature coefficient for the dura­tion of life or at least be able to show that if all other condi­tions are the same the dura­tion of life is for a given organism a func­tion of temperature. The writer307 investigated the dura­tion of life of fertilized and unfertilized eggs of Strongylo­centrotus purpuratus for the upper temperature limits.

TABLE XX

These observa­tions show a very high temperature coefficient near the upper temperature limit, and this may account at least partly for the fact that in tropical seas the pelagic fauna is so much more limited than in polar seas.308 It is quite probable that the high temperature coefficients at the utmost limits are only an expression of the coagula­tion time of certain proteins.

P. and N. Rau state that in the cold certain butterflies live longer, and similar statements exist for the silkworm, but these statements are not based on exact experi­ments, which are difficult. Dr. Northrop and the writer have started experi­ments on the influence of temperature on the dura­tion of life of the fly Drosophila. Newly hatched flies were kept first without food except water and air at 34°, 28°, 24°, 19°, 14°, and 10°, and second with cane sugar. The average dura­tion of life was as follows:

These experi­ments show that there is a definite temperature coefficient for the dura­tion of life and that this coefficient is of the order of magnitude of that of a chemical reac­tion. We are continuing these experi­ments with animals in the presence of food. It should, however, be remembered that the fly carries with it a good deal of reserve material from the larval period. We have carried on simultaneously determina­tions of the temperature coefficients of the dura­tion of the larval and pupa stage of these organisms at the same temperatures and found ratios similar to those given above for the dura­tion of life with water only.

7. Metchnikoff309 has furnished the scientific facts for our understanding of senescence. He has demonstrated that the changes in tissue which give rise to phenomena of senility are due to the action of phagocytes. Thus the ganglion cells are altered (digested?) and destroyed by “neuronophags” and this is the main cause of mental senility. Definite phagocytic cells, the osteoclasts, slowly dissolve the bones (by the excre­tion of an acid?) and this leads to the known fragility of the bones in old age. The whiteness of the hair is due to the action of phagocytes; in the muscles in old age the contractile elements are destroyed by the sarcoplasm, and so on. It agrees with these facts that where organs are absorbed in the embryonic development of an animal, as e. g., the tail of the tadpole in metamorphosis, the phenomenon is due to a process of phagocytosis (and autolysis). We have men­tioned the fact that in the larva of the Amblystoma the absorp­tion of the gills and of the tail occurs simultaneously and that both must be caused by a constituent of the blood. Such a constituent may be responsible for phagocytosis and autolysis in the organs undergoing absorp­tion. Metchnikoff calls atten­tion to the fact that certain infectious diseases, e. g., syphilis, may bring about precocious senility; and he men­tions also the senile appearance of young cretins which is due to the diseased thyroid. “It is no mere analogy to suppose that human senescence is the result of a slow but chronic poisoning of the organism.” He assumes that in man this poisoning is caused by the products of fermenta­tion in the large intestine and that the micro-organisms responsible for these fermenta­tions may therefore be regarded as the real cause of senility in man. Parrots which are long-lived birds have a limited flora of microbes in their intestine, while cows and horses which are short-lived in comparison with man possess an extraordinary richness of the intestinal flora. But, needless to say, it is not the quantity of microbes alone which is to be considered, the nature of the microbes is of much greater importance.

Certain plants like the Californian Sequoia gigantea may be considered as practically immortal since they live several thousands of years; other plants, the annuals, die after fructifica­tion. Metchnikoff quotes from a letter by de Vries that this author prolonged the life of Œnotheras by cutting the flowers before fertiliza­tion.

Metchnikoff suggests that it is a poison formed in the plant (in connec­tion with fructifica­tion?) which kills the annuals, while it is not formed or is less harmful in the perennials. He compares the situa­tion to the death of the lactic acid bacilli if the lactic acid is allowed to accumulate. This hypothesis is certainly worthy of considera­tion, and it is quite possible that in addi­tion to structural shortcomings poisons formed by certain organs of the body as well as poisons formed by bacteria account for the phenomenon of death in metazoa.

INDEX