Limb regeneration is one of the oldest topics within developmental biology, since the first experiments were reported in 1768 by Spallanzani, a Roman Catholic priest and Professor of Natural History at Padua, Italy. In his work Prodromo di un opera da imprimersi sopra la riproduzioni animali, he showed that regenerative ability was widespread throughout the animal kingdom, and that the legs and tails of newts could regenerate perfectly time after time. These studies provided much fuel to the contemporary debate between the preformationists and epigeneticists, and won for Spallanzani his election as a foreign correspondent of the Royal Society.

The Italian connection was crucial to the early development of regeneration research, because in 1823 Todd (1) showed that the regeneration of newt limbs was completely inhibited when the nerve supply to the limb was cut. Todd was a physician who served in the Royal Navy and apparently performed his experiments while at the British naval base in Naples. This was the first demonstration of the neurotrophic requirement for limb regeneration. As the 19th century progressed, the pace of regeneration research heated up, and by the turn of the century, there were hundreds of papers being published each year, mostly in German. Limb regeneration, along with studies on frog and newt eggs, were the driving forces in vertebrate developmental biology at that time. This pace continued throughout the first half of this century and from the 1930s researchers in the US made dominant contributions. In the last 20 yr, the pace has considerably slackened, since very few researchers have entered what has become an unfashionable field. Modern developmental biology is now dominated by Xenopus eggs and mouse genetics.

From: Methods in Molecular Biology, Vol. 97: Molecular Embryology: Methods and Protocols Edited by: P. T. Sharpe and I. Mason © Humana Press Inc., Totowa, NJ

Nevertheless, virtually all of the fundamental and fascinating questions that have intrigued students of limb regeneration for more than a century remain unanswered and are still there to inspire today's enquiring minds. Why can newts regenerate limbs and mammals cannot? What factors do the nerves supply? What factors does the epidermis supply? How do cells dedifferentiate and undergo transformation into another cell type? Are the mechanisms by which redifferentiation takes place the same as those that were used to develop the limb in the first place? Is the newly regenerated limb a different age from its contralateral unregenerated partner, and if so, is this a way to reverse the deleterious processes of aging?

Imagine what benefit the answers to these questions would bring to humankind. Indeed, there is already one good example of how limb regeneration studies have been of direct practical benefit to medicine. After limb amputation, the epidermis migrates over the stump to close the wound resulting in epider-mal/mesenchymal interactions, which are crucial to the induction of regeneration (see Subheading 2.2.). It has been known since 1906 (2) that if full thickness skin is sewn over the amputation plane regeneration is inhibited. This knowledge led to a change in surgical procedure in dealing with the amputated fingertips of children. Prior to Illingworth's report (3), such cases were dealt with by suturing the wound to make a cosmetically acceptable product, but one which was missing the terminal phalanx. Illingworth showed that if such amputations are simply covered and left to heal normally, then the terminal phalanx and nail will regenerate perfectly. Thus young children up to about the age of 11 yr have considerable capacity for regeneration of fingertips, provided the principles of regeneration are followed.

For more details on the subject of limb regeneration than can be included here, the reader is referred to a book by Wallace (4), which also contains much information on the older literature.

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