Richard J. Goss

The evolution of regeneration: Adaptive or inherent?

If regeneration were adaptive, it would have arisen autonomously by natural selection from non-regenerative antecedents. Unless each episode coincidentally reinvented the same method of regeneration independently, one would expect the various lineages to differ basically from each other, which they do not. On the other hand, if regeneration were inherent to metazoan life, a derivative of embryogenesis, its various expressions should be as much like each other as they resemble the development of embryonic appendage buds, which they do. It follows that the uneven distribution of regeneration must have been due to its extinction here and there, not as a negative adaptation by natural selection but as a pleiotropic epiphenomenon linked to more useful adaptations with which it was incompatible. In vertebrate evolution, these adaptations have included the transition from aquatic to terrestrial habitats and the modification of poikilothermic to homeothermic metabolism. The former advance rendered the regeneration of weight-bearing limbs impractical; the latter favored rapid wound healing and scar formation which effectively precluded blastema formation. If the latent capacity for regeneration persists in non-regenerative appendages, as would seem to be the case, then the restoration of its overt expression should be possible if the mechanisms of its inhibition could be discovered and eventually rendered ineffectual.

Tissue Relationships in the Development of Pedicles and Antlers in the Virginia Deer

Excision of skin from the presumptive pedicle region of fawns during the early months of life does not prevent the subsequent growth of pedicles and antlers. Removal of the osseous primordium of the frontal pedicle with or without the overlying skin completely arrests future development of the pedicle. The importance of the bony rudiment (or its adherent connective tissues) for successful pedicle formation is discussed in relation to the contrasting situation in the production of horns and antlers.

Induction of Extra Nephrons in Unilaterally Nephrectomized Immature Rats

Summary The normal number of glo-meruli per kidney in the rat rises from about 104 at birth to approximately 35 × 103 at 50 days of age. When one kidney is removed at birth the remaining one produces an average of 63 % more nephrons than normal by 70 days. Unilateral nephrectomy of successively older rats results in progressively less augmentation of the nephron complement in the remaining kidney up to 50 days, beyond which age the kidney loses its ability to produce new nephrons.

The Physiological Basis of Urinary Bladder Hypertrophy

Summary When both kidneys are removed from one partner of parabiosed rats, the unused bladder atrophies while that of the intact partner hypertrophies. This hypertrophy is brought about by a prompt and sustained increase of 30% in the frequency of micturition, together with a more gradual rise in the quantity of urine excreted at each voiding. The capacity of such bladders levels off at approximately double preoperative values by the fifth week, while the heightened frequency of urinations remains elevated. The two remaining kidneys of the intact rat undergo hypertrophy in compensation for the renal losses of its partner, but the degree of enlargement is less than half that observed in single rats deprived of one kidney.

Renal and Adrenal Relationships in Compensatory Hyperplasia.

Summary The compensatory renal hyper-plasia that normally follows unilateral ne-phrectomy is abolished by bilateral adrenal-ectomy if rats are maintained on fresh drinking water, but is restored when saline drinking water is provided or if such animals are injected with desoxycorticosterone. The adrenals are also important for the heightened proliferation caused by unilateral hydrone-phrosis. These experiments suggest that the role of the adrenal cortex in renal hyperplasia may be to secrete mineralocorticoids, which promote the retention of sodium and thereby stimulate cell division in the kidneys.

Disuse Atrophy of the Urinary Bladder After Bilateral Nephrectomy

Summary If both kidneys are removed from a rat which is kept alive by parabiosis to an intact partner, its unused bladder loses up to one-half the original weight. Such atrophic bladders persist indefinitely as organs composed mostly of dense fibrous connective tissue with attenuation of smooth muscle. In the intact partners, compensatory hypertrophy of both kidneys occurs, and the bladders become 50% larger than normal.

Modes of Growth and Regeneration

The development of an organism occurs in many ways. These include embryogenesis, compensatory growth, wound healing, and epimorphic regeneration. Some would classify cancer and aging as developmental processes as well. Each of these phenomena may be achieved by a variety of mechanisms, including mitosis, hypertrophy, migration, and differentiation at the cellular level of organization and the synthesis of chemical compounds at the molecular level. Atrophy, dedifferentiation, and molecular degradation are also important components of developmental processes. Even the demise of cells and tissues may be actively programmed into the scenario of development. Thus, the turnover of living material is a fundamental attribute of life. As such, it is as ubiquitous as life itself. Embryogenesis is also universal, at least among metazoan animals. Compensatory growth and wound healing are likewise common properties of virtually all cells, tissues, and organs, albeit to varying degrees of expression.

Why Study Ageing in Cold-Blooded Vertebrates?

Homeotherms exhibit programmed ageing correlated with their determinate mode of growth and the natural attrition of irreplaceable functional units in vitally essential organs. Poikilotherms are potentially capable of indefinite growth, can supplement their populations of functional units, and may therefore not be subject to the inherent depreciations of ageing. Comparative studies may enable us to determine which group is the exception to natures rule.

Adaptive Mechanisms of Growth Control

At a meeting in Rome in 1894, Professor Giulio Bizzozero (1894) speculated before his fellow pathologists that the various tissues and organs of the body might be classified according to their mitotic potentials. He referred to those tissues which are in a constant state of proliferation as elementi labili. In others, the cells multiply during maturation, but become mitotically stable in the adult. These he classified elementi stabili. Finally, elementi perenni included the nervous and muscular tissues, the cells of which are incapable of division beyond early stages of development. These categories have since come to be known as mitotically renewing, expanding, and static tissues, respectively (Figure 1).

The Right Size

The twentieth century has witnessed the accumulation of an impressive backlog of data on the details of growth mechanisms. As a result, we now have a wealth of information about how cells divide and enlarge, synthesizing DNA, RNA and proteins as they do so. Hardly a tissue has escaped the inquisitive explorations of students of regeneration and compensatory growth. From time to time, someone has ventured a hypothesis to explain how growth may be controlled, and every combination of inhibitor and stimulator seems to have been suggested (1). Out of this bewildering profusion of facts and theories, one would hope that a unifying hypothesis might emerge, one which will embrace all forms of growth from embryogenesis to the pathology of ageing, and all levels of organization from the subcellular to the organismal. It would be presumptuous to pretend that in our present state of ignorance the time has come for such a breakthrough. It would be inexcusable, however, if we did not continue our efforts to fathom the implications of growth. The unabashed speculation which follows is an attempt to paint a picture of growth not in the usual minute scientific detail but with broad strokes of the brush. In view of the generalizations inevitably to be included, however, the reader is reminded that “all generalizations are wrong, including this one.”