REGENERATION

in biology, the process by which some organisms replace or restore lost or amputated body parts. Organisms differ markedly in their ability to regenerate parts. Some grow a new structure on the stump of the old one. By such regeneration whole organisms may dramatically replace substantial portions of themselves when they have been cut in two, or may grow organs or appendages that have been lost. Not all living things regenerate parts in this manner, however. The stump of an amputated structure may simply heal over without replacement. This wound healing is itself a kind of regeneration at the tissue level of organization: a cut surface heals over, a bone fracture knits, and cells replace themselves as the need arises. Regeneration, as one aspect of the general process of growth, is a primary attribute of all living systems. Without it there could be no life, for the very maintenance of an organism depends upon the incessant turnover by which all tissues and organs constantly renew themselves. In some cases rather substantial quantities of tissues are replaced from time to time, as in the successive production of follicles in the ovary or the molting and replacement of hairs and feathers. More commonly, the turnover is expressed at the cellular level. In mammalian skin the epidermal cells produced in the basal layer may take several weeks to reach the outer surface and be sloughed off. In the lining of the intestines, the life span of an individual epithelial cell may be only a few days. The motile, hairlike cilia and flagella of single-celled organisms are capable of regenerating themselves within an hour or two after amputation. Even in nerve cells, which cannot divide, there is an endless flow of cytoplasm from the cell body out into the nerve fibres themselves. New molecules are continuously being generated and degraded with turnover times measured in minutes or hours in the case of some enzymes, or several weeks as in the case of muscle proteins. (Evidently, the only molecule exempt from this inexorable turnover is deoxyribonucleic acid which ultimately governs all life processes.) There is a close correlation between regeneration and generation. The methods by which organisms reproduce themselves have much in common with regenerative processes. Vegetative reproduction, which occurs commonly in plants and occasionally in lower animals, is a process by which whole new organisms may be produced from fractions of parent organisms; e.g., when a new plant develops from a cut portion of another plant, or when certain worms reproduce by splitting in two, each half then growing what was left behind. More commonly, of course, reproduction is achieved sexually by the union of an egg and sperm. Here is a case in which an entire organism develops from a single cell, the fertilized egg, or zygote. This remarkable event, which occurs in all organisms that reproduce sexually, testifies to the universality of regenerative processes. During the course of evolution the regenerative potential has not changed, but only the levels of organization at which it is expressed. If regeneration is an adaptive trait, it would be expected to occur more commonly among organisms that appear to have the greatest need of such a capability, either because the hazard of injury is great or the benefit to be gained is great. The actual distribution of regeneration among living things, however, seems at first glance to be a rather fortuitous one. It is difficult indeed to understand why some flatworms are able to regenerate heads and tails from any level of amputation, while other species can regenerate in only one direction or are unable to regenerate at all. Why do leeches fail to regenerate, while their close relatives, the earthworms, are so facile at replacing lost parts? Certain species of insects regularly grow back missing legs, but many others are totally lacking in this capacity. Virtually all modern bony fishes can regenerate amputated fins, but the cartilaginous fishes (including the sharks and rays) are unable to do so. Among the amphibians, salamanders regularly regenerate their legs, which are not very useful for movement in their aquatic environment, while frogs and toads, which are so much more dependent on their legs, are nevertheless unable to replace them. If natural selection operates on the principle of efficiency, then it is difficult to explain these many inconsistencies. Some cases are so clearly adaptive that there have evolved not only mechanisms for regeneration, but mechanisms for self-amputation, as if to exploit the regenerative capability. The process of losing a body part spontaneously is called autotomy. The division of a protozoan into two cells and the splitting of a worm into two halves may be regarded as cases of autotomy. Some colonial marine animals called hydroids shed their upper portions periodically. Many insects and crustaceans will spontaneously drop a leg or claw if it is pinched or injured. Lizards are famous for their ability to release their tails. Even the shedding of antlers by deer may be classified as an example of autotomy. In all these cases autotomy occurs at a predetermined point of breakage. It would seem that wherever nature contrives to lose a part voluntarily, it provides the capacity for replacement. Sometimes, when part of a given tissue or organ is removed, no attempt is made to regenerate the lost structures. Instead, that which remains behind grows larger. Like regeneration, this phenomenonknown as compensatory hypertrophycan take place only if some portion of the original structure is left to react to the loss. If three-quarters of the human liver is removed, for example, the remaining fraction enlarges to a mass equivalent to the original organ. The missing lobes of the liver are not themselves replaced, but the residual ones grow as large as necessary in order to restore the original function of the organ. Other mammalian organs exhibit similar reactions. The kidney, pancreas, thyroid, adrenal glands, gonads, and lungs compensate in varying degrees for reductions in mass by enlargement of the remaining parts. It is not invariably necessary for the regenerating tissue to be derived from a remnant of the original tissue. Through a process called metaplasia, one tissue can be converted to another. In the case of lens regeneration in certain amphibians, in response to the loss of the original lens from the eye, a new lens develops from the tissues at the edge of the iris on the upper margin of the pupil. These cells of the iris, which normally contain pigment granules, lose their colour, proliferate rapidly, and collect into a spherical mass which differentiates into a new lens. in biology, the process by which some organisms replace or restore lost or amputated body parts. Most organisms have a capacity for regeneration, although the extent of their abilities varies from that of simple planarian flatworms, which can grow an entire new body from a small strip of tissue, to the limited capacity of higher vertebrates to regenerate epidermal and other tissues in wound healing. Regeneration may occur in response to traumatic injury, as in human scar formation, or may be part of an animal's defense against predators (e.g., some lizards can release their tails when threatened and grow new ones). It may also be part of the seasonal turnover of certain structures, as in the molting of birds. Regeneration is closely related to vegetative reproduction, an important reproductive mechanism in plants and many lower animals. In most cases, cells that have already been differentiated into bone, muscle, skin, and other tissues lose their specialized nature and begin rapid growth once again, proliferating to form sufficient tissue to replace the missing part. After this proliferative phase, the cells again differentiate to form new cartilage, bone, muscle, and so on. A number of regenerative mechanisms have been evolved by different species. Autotomy, the spontaneous loss and replacement of a body part, occurs in many insects and crustaceans, and enables them to shed a crippled leg or claw. The discarded body part usually breaks off at a predetermined site; in some, the new part is an exact replica of the lost structure, while in others, as in the lizard, the new part is functionally similar but anatomically different from the lost part. Compensatory hypertrophy, in which the tissues that are left behind grow larger to overcome the handicap of the loss, also occurs in a variety of species. An example is the ability of the human liver to grow larger when one or more of the lobes is lost to surgery, disease, or injury; the regenerating liver does not duplicate the missing lobes but creates sufficient tissue in the remaining lobes to replace the lost function. Some part of the original organ must remain for this process to take place. In a third type of regeneration, metaplasia, tissues that have been adapted to one function become altered to fulfill the function of the lost structure. There may be no remnant of the original organ, so that nearby structures must take its place; an example is the conversion of pigmented iris tissues to replace the loss of the lens in certain amphibians. Regeneration is considerably more common in lower plants and simple multicellular animals. Plant regeneration usually takes place by morphallaxis, in which neighbouring cells multiply and reorganize to take the place of the missing tissue. In most multicellular animals that regenerate, the first step is the formation of a blastema, a bud of relatively undifferentiated cells that gradually develops into the replacement part. If this blastema is moved or otherwise manipulated in the laboratory, it is possible to form an abnormal structure (e.g., two heads on a flatworm). The causes of regeneration in particular species and the inability of some closely related organisms to regenerate lost tissues are still not clear. In higher animals it appears that nerves supplying the missing structure must be present to stimulate regrowth; thus it appears that regeneration serves functional needs, occurring only when the physiological or structural function of a body part must be replaced. On the other hand, complete loss of the structure may not be necessary, although some injury must have occurred to stimulate regeneration. In some animals a limb may be partially severed, causing a second complete limb to grow next to the injured one. Regenerating tissues also apparently follow a strict polarity, growing back in the proper orientation to the rest of the body. Since the most commonly lost structures are limbs and tails, the pattern of growth is usually outward from the body, suggesting that tissues more proximal than the injury contain all the necessary information to replace the lost part, but not those closer to the main trunk of the body. In some cases, however, as in fish fins, regeneration may occur in both directions. Regeneration is most common in invertebrates, occurring in almost all coelenterates and planarians, most annelids (segmented worms), and many insects. Among vertebrates, limited regeneration of limbs occurs in most fishes and salamanders, and tail regeneration takes place in larval frogs and toads (but not adults) and several reptile species. Although feather replacement may be considered a form of regeneration, few birds have the capacity to regenerate more complex structures. No mammals have the ability to regrow lost limbs or tails, but some species can regenerate other peripheral appendages, (e.g., a deer's antlers) or internal organs (e.g., the human liver). Additional reading Biological regeneration is explored by Charles E. Dinsmore (ed.), A History of Regeneration Research: Milestones in the Evolution of a Science (1991), a well-organized, readable review of animal regeneration studies, based on a 1988 symposium; John F. Fallon et al. (eds.), Limb Development and Regeneration, 2 vol. (1993), emphasizing the role of tissue interactions in orchestrating molecular expression during growth and pattern formation; Frederick J. Seil (ed.), Neural Regeneration (1994), highly technical symposium papers reporting recent advances made in this field; John G. Nicholls The Search for Connections: Studies of Regeneration in the Nervous System of the Leech (1987), a short, highly readable monograph; Harry J. Buncke (ed.), Microsurgery: TransplantationReplantation: An Atlas-Text (1991); Gerald Weissmann (ed.), The Cell Biology of Inflammation (1980); David Evered and Julie Whelan (eds.), Fibrosis (1985), symposium papers; Robert P. Mecham (ed.), Regulation of Matrix Accumulation (1986); Elizabeth D. Hay (ed.), Cell Biology of Extracellular Matrix, 2nd ed. (1991); and Erkki Ruoslahti and Eva Engvall (eds.), Extracellular Matrix Components (1994).