Mythology, Evolution, and Tissue Regeneration

Although the technology may be just emerging, regeneration of body parts is hardly a new concept. Through the myth of Prometheus, the ancient Greeks are credited with knowledge of the liver's natural regenerative powers. As punishment for stealing the secret of fire from the gods of Olympus, Prometheus was condemned to having a portion of his liver eaten each day by an eagle. His liver would regenerate overnight, providing the eagle with an endless food source and Prometheus with eternal torture. The regenerative capability of a real living creature was recorded as early as 330 BC, when Aristotle observed that a lizard could grow back the lost tip of its tail. In the late 1700s, the scientist Spallanzani reported that a newt could regenerate a complete limb. Since then, the study of regeneration in lower life forms has laid the groundwork for understanding the regenerative capabilities and potential of humans.

Bacteria and the single-celled protozoans regenerate complete organisms with each cell division. Many multicellular invertebrates also exhibit extensive regenerative abilities. When cut in half, the at-worm Planaria can grow a new head from one piece and a new tail from the other. However, progression up the evolutionary ladder is generally accompanied by a reduction in regenerative capacity.

Limb of Newt, Horn of Stag, Wing of Bat

Two of nature’s true regenerators

The pinnacle of vertebrate regeneration takes place in the urodele amphibians (salamanders and newts). When a newt's forearm or hindleg is severed, a new one forms in about six weeks. If half of the lower jaw is lost, it grows back complete with new teeth. The process through which this new growth takes place provides insights into some key differences between amphibian regeneration and mammalian wound repair.

After a newt limb is amputated, the wound is sealed over by the rapid migration of epithelial cells from surrounding tissue. Mesodermal cells beneath the epidermis lose their differentiated character and reproduce to form a conical mound of cells called the blastema. The blastemal cells eventually redifferentiate into the cartilage, connective tissue, and muscle of the new limb. Signals exchanged between the epidermal and mesodermal cells control the reversal of the differentiated state and subsequent regeneration. Much speculation has centered on whether a similar process can be duplicated in mammals.

While mammals have retained the ability to regenerate certain tissues, such as liver, they lack the ability to grow new limbs through blastema formation. But has major regenerative capacity in mammals been lost over the course of evolution, or is it lying dormant waiting for its potential to be unlocked? The basic ability may still be present even though the appropriate trigger mechanisms may not be. Assuming that the same genes that form structures in the developing embryo are also responsible for their regeneration in the adult, the task of scientists is to determine the nature of the blockades and to remove or bypass them. There are several tantalizing examples where mammals have not relinquished the ability to regenerate. The most conspicuous example of mammalian regeneration is the annual replacement of antlers in deer. This is the only example of complete regeneration of mammalian appendages. Other notable examples include bats being able to plug holes in their wing membranes; rabbits, domestic cats, and bats filling in ear holes, and regrowth of the tips of mouse toes. The prospects for human regeneration were greatly enhanced by the discovery that amputated fingertips could grow back in young children.

Even though humans and other mammals cannot on their own regenerate teeth, limbs, and organs, specific tissues possess considerable recuperative powers. Mammals are continuously replacing cells in tissues derived from the protective layer of surface epithelium. Appendages such as skin, nails, and hair grow almost continuously. Teeth are constantly replaced in lower vertebrates, but in mammals are shed once and then replaced with a permanent set. However, if the roots remain open as in the case of rodents, the teeth may continue to grow throughout the life of the animal. Other tissues with tremendous cell turnover include blood, intestinal epithelium, and liver. In the intestine, the entire epithelium of each villus turns over every 2 3 days. It is estimated that the total daily production of the various blood cells is in the order of 3 x 1,011 cells for a 150 pound person.

In most vertebrates, true regeneration is limited to a very few tissues, such as liver, bone, and skeletal muscle. Liver cells come closest to mimicking the urodele regeneration phenomenon, in which differentiated cells revert to an embryonic dividing state and then differentiate once more into specialized cells. Mature liver cells only partially dedifferentiate, however. In response to tissue destruction, liver cells, which normally don't reproduce, undergo rapid cell division. In true Promethean style, these remarkable cells continue to carry out their normal metabolic functions while multiplying to replace lost tissue. A rat can replace two-thirds of its liver in 5 to 7 days. A baboon liver transplanted into a human will double in size to reach that of a human liver within a week.

Other tissues rely on stem or progenitor cells undifferentiated embryonic-type cells that are present in most, perhaps all, adult tissues. Stems cells are dormant until called into action by the proper set of chemical signals, whereupon they differentiate to form the required tissues. However, tissues differ greatly in the effectiveness of their stem cells. Of the major tissues that form the craniofacial complex, (nerve, muscle, skin, bone, blood, cartilage) bone is the most versatile in its regenerative capabilities.