Regeneration

In amphiuma the feet are not used by the animal as organs of locomotion, since they are too small and weak to support the heavy body. They can be moved by the animal in the same way that the feet are moved in other forms, and yet are useless for progression. It is said by Schreiber that the regeneration of the legs of Triton marmoratus is relatively very slight as compared with that of other forms. Fraisse also found in this form that an amputated leg did not grow again, only a deformed stump being produced. The tail also is said to regenerate to only a slight extent, but, so far as I know, there is nothing peculiar in the life of this form that makes it less liable to injury than other large urodeles.1 Weismann cites the case of proteus, which is said also to regenerate less well than do other forms. It lives in the caves of Carniola, where there are few other animals that could attack or injure it, and to this immunity is ascribed its lack of power of regeneration ; yet Goette states that he observed a regenerating leg in this form, but that the process was not complete after a year and a half. In necturus also, which is not protected in any way, regeneration is equally slow. Frogs are unable to regenerate their limbs, although they are sometimes lost, but the larval tadpole can regenerate at least its hind legs. In the lizards the tail regenerates, but at present we do not know of any connection between this condition and the liability of certain forms to injury. Turtles and snakes do not regenerate their tails. I do not know of any observations on crocodiles.

In birds, the legs and wings are not supposed to have the power to regenerate,2 but in two forms 3 at least the beak has been found to 1 I do not know whether this animal was kept long enough to make it certain that the legs do not regenerate. 2 A statement to the contrary quoted in Darwin's Animals and Plants under Domestication is doubted by Darwin himself. possess remarkable powers of regeneration. There are a few very dubious observations in regard to the regeneration in man of superfluous digits that had been cut off.1

These examples might be added to by others in the groups cited, and also by examples taken from the smaller groups of the animal kingdom, but those given will suffice, I think, to show that the power to regenerate is characteristic of entire groups rather than individual species. When exceptions occur, we do not find them to be forms that are obviously protected, but the lack of regeneration can rather be accounted for by some peculiarity in the structure of the animal. If this is borne in mind, as well as the fact that protected and unprotected parts of the same animal regenerate equally well, there is established, I think, a strong case in favor of the view that there is no necessary connection between regeneration and liability to injury. We may therefore leave this side of the question and turn our attention to another consideration.

It will be granted without argument that the power of replacement of lost parts is of use to the animal that possesses it, especially if the animal is liable to injury. Cases of usefulness of this sort are generally spoken of as adaptations. The most remarkable fact in connection with these adaptive responses is that they take place, in some cases at least, in parts of the body where they can never, or at most very rarely, have taken place before, and the regeneration is as perfect as when parts liable to injury regenerate. Another important fact is that in some forms the regeneration is so slow that if the competition amongst the animals was very keen those with missing legs, or eyes, or tails, would certainly succumb ; yet, if protected, they do not fail to regenerate. If, therefore, the animal can exist through the long interval that must elapse before the lost part regenerates, we cannot assume that the presence of the part is of vital importance to the animal, and hence its power to regenerate could scarcely be described as the result of a "battle for existence," and without this principle " natural selection " is powerless to bring about its supposed result.

It is extremely important to observe that some cases, at least, of regeneration are not adaptive. This is shown in the case where a new head regenerates at the posterior end of. the old one in P lamina htgubris, or where a tail develops at the anterior end of a posterior piece of an earthworm, or when an antenna develops in place of an eye in several Crustacea. If we admit that these results are due to some inner laws of the organism, and have nothing to do with the relation of the organism to its surroundings, may we not apply the same principle to other cases of regeneration in which the result is useful ?

So firm a hold has the Darwinian doctrine of utility over the thoughts of those who have been trained in this school, that whenever it can be shown that a structure or a function is useful to an animal, it is without further question set down as the result of the death struggle for existence. A number of writers, being satisfied that the process of regeneration is useful to the animal, have forthwith supposed that, therefore, it must have been acquired by natural selection. Weismann has been cited as an example, but he is by no means alone in maintaining this attitude. It would be entirely out of place to enter here into a discussion of the Darwinian theory, but it may be well worth while to consider it in connection with the problem of regeneration.

We might consider the problem in each species that we find capable of regenerating ; or, if we find this too narrow a field for our imagination, we might consider the process of regeneration to have been "acquired by selection in the lower and simpler forms," and trace its subsequent progress as it decreased in the course of phylogeny " in correspondence with the increase in complexity of organization," or with the decrease of exposure to injury. At the risk of adopting the narrower point of view I shall confine the discussion to the possibility of regeneration being acquired, or even augmented, through a process of natural selection in any particular species.

The opportunity to regenerate can only occur if a part is removed by accident or otherwise. On the Darwinian theory we must suppose that of all the individuals of each generation that are injured, /';/ exactly the same part of the body, only those have survived or have left more offspring that have regenerated. In order that selection may take place, it must be supposed that amongst these individuals injured in exactly the same region, regeneration has been better in some forms than in others, and that this difference is, or may be, decisive in the competition of the forms with each other. The theory does not inquire into the origin of this difference between individuals, but rests on the assumption of individual differences in the power to regenerate, and assumes that these differences can be heaped up by the survival and inbreeding of the successful individuals; i.e. it is assumed that, by this picking out or selection through competition in each generation of the individuals that regenerate best, the process will become more and more perfectly carried out in the descendants, until at last each part has acquired the power of complete regeneration.

There are so many assumptions in this argument, and so many possibilities that must be realized in order that the result shall follow, that, even if the assumptions were correct, one might still remain sceptical in regard to the possibilities ever becoming realized. If we examine somewhat more in detail the conditions necessary to bring about this supposed process, we shall find ample grounds for doubt, and even, I think, for denial that the results could ever have been brought about in this way.

In the first place, the assumption that the regeneration of an organ can be accounted for as a result of the selection of those individual variations that are somewhat more perfect, rests on the ground that such variations occur, for the injury itself that acts as a stimulus is not supposed to have any direct influence on the result, i.e. for better or worse. All that natural selection pretends to do is to build up the complete power of regeneration by selecting the most successful results in the right direction. In the end this really goes back to the assumption that the tissue in itself has power to regenerate more completely in some individuals than in others. It is just this difference, if it could be shown to exist, that is the scientific problem. But, even leaving this criticism to one side, since it is very generally admitted, it will be clear that in many cases most of the less complete stages of regeneration that are assumed to occur in the phyletic series could be, in each case, of very little use to the individual. It is only the completed organ that can be used ; hence the very basis of the argument falls to the ground. The building up of the complete regeneration by slowly acquired steps, that cannot be decisive in the battle for existence, is not a process that can be explained by the theory.

There is another consideration that is equally important. It is assumed that those individuals that regenerate better than those that do not, survive, or at least have more descendants ; but it should not be overlooked that the individuals that are not injured (and they will belong to both of the above classes) are in even a better position than are those that have been injured and have only incompletely regenerated. The uninjured forms, even if they did not crowd out the regenerating ones, which they should do on the hypothesis, would still intercross with them, and in so doing bring back to the average the ability of the organism to regenerate. Here we touch upon a fatal objection to the theory of natural selection that Darwin himself came to recognize in the later editions of the Origin of Species, namely, that unless a considerable number of individuals in each generation show the same variation, the result will be lost by the swamping effects of intercrossing. If this be granted, there is left very little for selection to do except to weed out a few unsuccessful competitors, and if the same causes that gave origin to the new variation on a large scale should continue to act, it will by itself bring about the result, and it seems hardly necessary to call in another and questionable hypothesis.

Finally, a further objection may be stated that in itself is fatal to the theory. We find the process of regeneration taking place not only at a few vulnerable points, but in a vast number of regions, and in each case regenerating only the missing part. The leg of a salamander can regenerate from every level at which it may be cut off. The leg of a crab also regenerates at a large number of different levels, and apparently this holds for all the different appendages. If this result had been acquired through the action of natural selection, what a vast process of selection must have taken place in each species 1 Moreover, since the regeneration may be complete at each level and in each appendage without regard to whether one region is more liable to injury than is another, we find in the actual facts themselves nothing to suggest or support such a point of view.

If, leaving the adult organism, we examine the facts in regard to regeneration of the embryo, we find again insurmountable objections to the view that the process of regeneration can have been produced by natural selection. The development of whole embryos from each of the first two or first four blastomeres can scarcely be accounted for by a process of natural selection, and this is particularly evident in those cases in which the two blastomeres can only be separated by a difficult operation and by quite artificial means. If a whole embryo can develop from an isolated blastomere, or from a part of an embryo without the process having been acquired by natural selection, why apply the latter interpretation to the completing of the adult organism ?

Several writers on the subject of regeneration in connection with the process of autotomy (or the reflex throwing off of certain parts of the body) have, it seems to me, needlessly mixed up the question of the origin of this mechanism with the power of regeneration. If it should prove true that in most cases the part is thrown off at the region at which regeneration takes place to best advantage, it does not follow at all that regeneration takes place here better than elsewhere, because in this region a process of selection has most often occurred. The phenomenon of regeneration in the arm of the starfish, that has been described on a previous page, shows how futile is an argument of this sort. If, on the other hand, the autotomy is supposed to have been acquired in that part of the body where regeneration takes place to best advantage, then our problem is not concerned with the process of regeneration at all, but with the origin of autotomy. If the attempt is made to explain this result also as the outcome of the process of natural selection acting on individual variations, many of the criticisms advanced in the preceding pages against the supposed action of this theory in the case of regeneration can also readily be applied to the case of autotomy. In Chapter VIII, in which the theories of autotomy are dealt with, this problem will be more fully discussed.

IT is a more or less arbitrary distinction to speak of internal in contrast to external organs, since the latter contain internal parts ; but the distinction is, for our present purposes, a useful one, especially in regard to the question of regeneration and liability to injury. In this connection we shall find it particularly instructive to examine those cases of regeneration of internal organs that cannot be injured, under natural conditions, without the animal itself being destroyed. An illustration of this may be given. The liver, or the kidney, or the brain of a vertebrate can seldom be exposed to accidental injury without the entire animal being destroyed, although, of course, diseases of various kinds may injure these organs without destroying the animal, but cases of the latter kind are not common.

The experiments made by Ponfick ('90) on the regeneration of the liver in dogs and in rabbits gave the most striking results. Ponfick found after removal of a fourth, or of a half, or even, in a few successful operations, of three-fourths of the liver, that, in the course of four or five weeks, the volume of the remaining part increased, and in the most extreme case, to three times that of the piece that had been left in the body. The first changes were found to have begun as early as thirty hours after the operation, when the liver cells had begun to divide. The maximum number of dividing cells was found about the seventh day, and then decreased from the twentieth to the twenty-fifth day, but cells were found dividing even on the thirtieth day. These dividing cells appeared everywhere throughout the liver, and were no more abundant at the cut-edges than elsewhere. There takes place, in consequence, an increase in the volume of the liver, rather than a replacement of the part that is removed. The increase takes place in the cells of the old part, the lobules swelling up to two, three, or even four times their former size. No new liver lobules seem *:o be formed. The old tubules of the liver also becom-; larger, owing to an increase in the number of their cells. Since the change takes pl.ace in the old part, and is due to an increase in size of the

lobules, tubes, etc., the process is spoken of as one of hypertrophy rather than of regeneration. Kretz found a case in which the entire parenchyma of the liver seemed to have been destroyed, presumably by a poison from some micro-organism, and later a regeneration of the tissue had taken place. If this conclusion is correct, it shows that sometimes an internal organ may meet with an injury that does not directly destroy the rest of the body, and the animal may survive.

The regeneration of the salivary gland of the rabbit described by Ribbert is another example of an internal organ that can seldom be injured, and yet can be replaced after artificial removal. Weismann ('93) has recorded an experiment in which half of a lung of triton was cut off. After fourteen months the lung had not been restored in four individuals, and in one " it was doubtful whether a growth of the lung had not taken place, but even in this case it had not recovered its long, pointed form."

The regeneration of the eye in triton was first made known by Bonnet. The right eye was partly cut out, and after two months it had completely regenerated. Blumenbach, in 1784, removed the anterior part of the bulb of the eye of " Lacerta lacustris." Six months later a smaller bulb was present. Phillipeaux (*8o) found that if the eye of an aquatic salamander was not entirely removed, a new eye regenerated ; but if the eye was completely extirpated a new eye did not appear. Colucci, in 1885, described the regeneration of the lens of the eye of triton from the edge of the optic cup. Wolff, later, independently, discovered the same fact, and it has been more recently confirmed by E. Miiller ('96), W. Kochs ('97), P. Rothig ('98), and Alfred Fischel ('98). The most important part of this discovery is that the new lens develops from the margin of the optic cup, and not from the outer ectoderm, as it does in the embryo. This result will be more fully discussed in a later chapter. It is highly probable in this case that the regeneration stands in no connection whatsoever with the liability of the eye to injury, for of the large number of salamanders that have been examined, none has been found with the eye mutilated. The position of the eye is such that it is well protected from external injury, and the tough cornea covering its outer surface would also further protect it from accidental injury. When we recall the high degree of structural complexity of the eye, its capacity to regenerate, if only a portion of the bulb is left, and its powet to replace the lens if this is removed are certainly very remarkable facts. We find here, I think, an excellent refutation of the incorrectness of the general assumption of a connection between regeneration and liability to injury. Moreover, since there is no evidence whatsoever to show that the eyes in these animals 'ire ever

subject to diseases caused by bacteria, and much evidence to show that they are not so injured, we are still further confirmed in our general conclusion. It has been known for a long time that even in man the lens of the eye is sometimes regenerated after its removal. The regeneration has been supposed to take place from the old capsule of the lens, or possibly from a piece of the lens left after the operation ; but whatever its origin, the fact of its regeneration in man, and in other mammals also, is a point of some interest in this connection.

Podwyssozki ('86) found that regeneration may take place in the kidney of certain mammals, — best in the rat, more slowly in the rabbit. The restoration of the lost part takes place first by replacement of the epithelium. The old canals may then push out into the connective tissue that accumulates in the new part, but there is no new formation of canals or of glomeruli. According to Podwyssozki the regeneration of the kidney is less complete than that of any other gland. Peipers has reinvestigated the subject, and his results agree in the main with those just given. He finds in addition that new canals may grow out from the old ones into the new part.

Podwyssozki and Ribbert ('97) have found that the salivary gland has a remarkable power of regeneration. Ribbert removed a half (or even more than this) of the salivary gland of the rabbit. In the course of two or three weeks new material had developed over the cut-surface. In one case at least five-sixths of the gland had been taken out, and at the end of three weeks the gland had regenerated to its full size. Microscopic examination showed that the greater part of the gland was made up of new lobes, some of which were as large as, others smaller than, the normal lobes. The new part contained new tubes with terminal acini. These had arisen from the tubes of the old part. The connective tissue of the new part also came from that of the old. In this case a true process of regeneration takes place from the cut-surface ; in addition a certain amount of enlargement, or hypertrophy, also takes place in the old part. Ribbert believes there is a connection between the process of hypertrophy and of regeneration of such a kind that the more active the one, the less active the other.

Regenerative changes are known to occur in other internal organs besides these glandular ones. Broken bones are united, if brought in contact, by a process that involves a certain amount of regeneration. Although new bony tissue may be formed at the region of union, the bones of mammals and of birds do not seem able to complete themselves, if a part is removed, except to a limited extent. While the broken bones of the leg or of the arm have the power of reuniting if held for some time in place, yet in nature this condition can seldom

be fulfilled, and the animal with a broken leg or wing will most probably be killed. Nevertheless, since the bones have this power at whatever level they may be broken (but only if they are kept together artificially), the process can scarcely have been acquired through the liability of the parts to injury. We find here another instance of a useful process existing in animals, but one that could not have been acquired by exposure of the part to injury. It is probable that this same property is found in all the bones of the body, — in those that may occasionally be injured, and in those that are not.

The muscles have also the power of regenerating, although few experiments have been made except in those forms in which the whole leg can regenerate, yet there are a few observations that show that even in mammals, in which the leg or the arm cannot regenerate as a whole, a certain amount of regeneration of the muscles themselves may take place. It has been known for a long time that if a nerve is cut a new nerve grows out from the cut-end, and may extend to the organs supplied by that nerve. The process takes place more successfully if the peripheral part is left near the cut-end from which the new nerve grows. Whether this old part only serves to guide the new part to its proper destination, or whether it may also contribute something to the new nerve, as, for instance, cells for the new sheath, is not finally settled. The general opinion in regard to the origin of the new nerve fibres is that the central axis or fibril grows from the cut-end. That this power could have been acquired for each nerve as a result of its liability to injury is too improbable to discuss seriously.

The central nervous system of the higher vertebrates s,eems to have very little power of regeneration, and although in some cases a wounded surface may be covered over and a small amount of connective tissue be formed, the development of new ganglion cells does not seem to occur. In other animals, as the earthworm, planarian, and even in the ascidian, as shown by Loeb, a new entire brain may develop after the removal of the old brain, or of that part of the body in which it is contained.

This examination of the power of regeneration of internal organs in the vertebrates has shown that it is highly improbable that there can be any connection between their power of regeneration and their liability to injury. That the internal organs may be occasionally injured by bacteria, or by poisons made in the body, may be admitted, but that injuries from this source have been of sufficient frequency to establish a connection, if such were indeed possible, between their power of regeneration and their liability to injury from these causes is too improbable a view to give rise to much doubt. These results taken in connection with those discussed in the preceding chapter go

far toward disproving the view that the power of regeneration has a connection with the liability of a part to injury. The hypertrophy, or unusual enlargement, of organs has long attracted the attention of physiologists, and the extremely interesting observations and experiments that have been made in this connection have an important although an indirect bearing on the problem of regeneration. Ribbert, as has been pointed out, holds that the processes of hypertrophy and of regeneration stand in a sort of inverse relation to each other, but it is doubtful, I think, if any such general relation exists. Two kinds of hypertrophy are now generally distinguished : functional hypertrophy, which takes place when a part becomes enlarged through use ; and compensating hypertrophy, which takes place when one organ being removed another enlarges. The enlargement in the latter case may, of course, be brought about by the increased use of the parts that enlarge, but as this is not necessarily the case, the distinction between the two processes is a useful one. The causes of compensating hypertrophy are by no means simple, and several possibilities have been suggested to account for the enlargement. The best ascertained facts in connection with hypertrophy relate almost entirely to man and to a few other mammals.1

By hypertrophy is meant an increase of the substance of which an organ is composed. Swelling due to the imbibition of water or of blood-serum is not, in a technical sense, a process of hypertrophy. Virchow distinguishes two kinds of hypertrophy: (i) Hypertrophy in a narrower sense in which the enlargement is due to an increase in the size of the cells of which an organ is composed. This enlargement of the individual cells leads of course to an increase in the size of the whole organ. (2) Hyperplasy due to an increase in the number of cells of which an organ is composed, which also causes an enlargement of the whole organ if the cells retain the normal size. The division into functional and compensating hypertrophy given above is a physiological distinction, and both of these processes might occur in Virchow's subdivisions.

Giants may be looked upon as hypertrophied individuals, since all the organs of the body are larger than the normal. The enlargement is, in this case, not due to external influences, but to some peculiarity 1 The more generally accepted results are given in Virchow's Cellular Pathology and in Ziegler's Pathological Anatomy. An excellent review of the subject down to 1895 is given in a summary by Ludwig Aschoff in the Ergebnisse d, allgetn. patholog. Morphol, nnd Physiologic, 1895, "Regeneration und Hypertrophie," in which there are two hundred and eighteen references to the literature.