Lewis Wolpert: The Sceptical Inquirer

We have much to learn from salamanders
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The Independent Online

The story fed to the media relates to a £10m grant to a team at the University of Manchester from The Healing Foundation charity to investigate certain animals for clues as to how the body can regenerate and heal wounds without scarring. But how realistic is the possibility of limb regeneration in humans?

We have much to learn from salamanders, who have amazing powers of regeneration that include limbs, upper and lower jaws, the lens and retina of the eye, and sections of the heart. Why they have these abilities still lacks a good evolutionary explanation. One might think that regeneration of a limb merely repeats the developmental mechanisms that led to the growth of the limb in the embryo. But the scale is so very different. The result of limb amputation in the salamander is the formation of a mound of cells, the blastema, at the cut surface that will eventually give rise to the rest of the limb; but it is enormous compared with the embryonic limb. This difference in scale is crucial and the mechanisms involved are not understood.

A key feature of regeneration of the limb is the identity of the cells in the blastema. They have a sense of position and they use this to pattern the blastema - in other words, to decide the shape and size of the limb to be regrown. The cells in the blastema give rise only to structures between the cut and the tips of the digits - there is no signal from the stump as to what they should do. The cells thus need to know where they are along the axis from the shoulder to the hand (the proximodistal axis). This sense of position, positional value, can be changed with chemical treatment, and can make them think they are closer to the shoulder and develop unnecessary structures like two elbows. An exciting recent discovery is the presence of a protein that is graded along the proximodistal axis and so may be the molecular basis of positional value. But there are two other axes whose molecular basis is unknown.

It is going to be very difficult to obtain cells from an individual who has lost a limb and then modify them so that they will behave like the blastema cells of the salamander when injected at the site of the lost limb. Embryonic stem cells could provide a beginning, but that is in itself tricky. Then, many genes will have to be turned on and off so that the right proteins are present, and the cells generate the missing structures. In the long run, it might, perhaps, not be impossible. For, while this is not well known, humans can regenerate the tips of their fingers provided the nail is there.

The other part of this new initiative is scarless wound healing, which is marginally less difficult. Normal wound healing leads to the formation of a permanent scar in adult skin. By contrast, the skin of the embryo undergoes scarless repair. Normally, the repair process in the adult skin begins with an acute inflammatory response and one of the most important aspects of scarless foetal wound repair appears to be a lack of inflammation. But the mechanism of foetal wound healing remains largely unknown.

It is a field with an exciting future, but we must avoid swallowing too much hype.

Lewis Wolpert is emeritus professor of biology as applied to medicine at University College London

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