Embryology Biology 441 Spring 2011 Albert Harris
Notes on Regeneration
Salamanders, especially the sub-group of salamanders called newts, can regenerate their legs. Their legs are not really simpler than mammal legs. So it is a good question why humans can't grow back arms and legs that somehow got cut off? Maybe researchers will discover some fundamental reason why it will forever be fundamentally impossible for mammals to regenerate legs and arms. Another possibility is that one of you in this class will discover a method to stimulate regrowth of arms and legs. A specific question is whether differentiated cells switch from one cell type to another (for example, whether descendants of skeletal cells sometimes become muscle cells, etc.) The ability of cells to switch from one cell type to another could possibly be the limiting variable, needed for limb regeneration to occur! However, radioactive labeling studies on salamander leg regeneration show that skeletal cells " dedifferentiate" in the " blastema" but then always redifferentiate back into skeletal cells; likewise, muscle cells seem to dedifferentiate, but when they redifferentiate they only become muscle; also skin cells become skin etc. It seems to me (but I would welcome counter-arguments) that if all the skeletal cells of a regenerated leg are descended from cells that had been skeletal cells in the stump of the cut off leg, and ditto for muscle cells, skin cells, endothelial cells, etc. then wouldn't that mean that regeneration of limb structures amounts to a form of cell sorting? The descendants of cells that had been part of the femur, first dedifferentiate, then divide, and then redifferentiate as skeletal cells, but this redifferentiation is somehow in the geometric pattern of the radius and the ulna, and also the geometric patterns of wrist bones, finger bones etc. Likewise, for muscles, cells that had been part of biceps muscles would seemingly dedifferentiate, then divide to help form the blastema, and when they redifferentiate somehow form the geometric pattern of muscles in the lower arm. Is this situation analogous to H. V. Wilson misinterpreting the reformation of dissociated sponges as being caused by cells switching from being one cell type to being a different cell type, according to their new locations? What do you think? You don't need to agree with me! Just understand the issue. Serious medical journal articles have reported successful regeneration of the last joint of human fingers, as long as the cut stump isn't too tightly bandaged. Another good question is why cuts and scratches heal so much faster in children than they do in adults. If you want a demonstration of this phenomenon, all you need to do is to take some children black-berry picking! You and they will get lots of scratches on your hands and arms, from the thorns. 3 or 4 days later, your scratches will have begun the process of healing, and the kids' scratches will have healed. I speak from personal experience on this; the contrast is amazing; and you know for sure that you and the children got the scratches at the same time. Does regeneration require removal of some inhibitory signal? At least one researcher has proposed that skin produces an inhibitor of its own growth and regeneration. Analogous to the way in which auxin was first invented as a hypothetical substance, and then eventually isolated and identified by means of a bioassay, can you invent a bioassay to detect and compare amounts of s substance that inhibits skin cells from growing and dividing? A British researcher invented the name "chalone" for this hypothetical self-inhibitor of skin growth. He pulled away the outer layers of mouse skin (epidermis), and measured increases in rates of growth and division of the basal layers of epidermis. Then he tested chemicals isolated from skin and fractionated, for example by chromatography and/or electrophoresis. He reported some positive data, indicating that he was getting close to the discovery of some one particular substance, used by skin to inhibit its own growth rates. But chalone still has not been proven to exist. Maybe a mixture of chemicals produce the effect; maybe the real mechanism works by destroying a self-stimulating substance. Maybe the answer to regenerating legs and arms will depend on discovering what mechanism inhibits tissues from growing too much, until tissues are removed? Can you invent a (potentially!) practical bioassay for such a hypothetical self-inhibitory substance, for salamander limb buds? In terms of the existence and sensitivity of limb tissues to such a self-inhibitory substance (that is, IF it really existed, and IF reduction in amounts of such a self-inhibitory substance actually was how limb regeneration was caused and controlled) how would you explain the greater regeneration ability of salamander legs, as compared with human leg? If such a substance really was the means of control of leg regeneration, suggest research that could lead to practical medical treatments that could cause regeneration of human arms and legs.
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