An eye for an eye

A limb removed from a mammal never regrows. But subject a newt, and a range of other creatures like it, to the same treatment and, eventually, the missing leg will regenerate. The same is true of other body parts too. But how long can these animals keep up this feat? And does it eventual fail, or are the regenerated parts as good as new? To find out, Panagiotis Tsonis and his colleagues have now done the incredible experiment of removing the lenses from the eyes of the same newts for 19 years in succession, as he explained to Chris Smith...

Panagiotis - The experiment was to remove the legs from the same animal 19 times so we have this leek in the cornea, we remove the lens, the cornea heals within a day and then the lens regenerates from the iris within 30 to 40 days.

Chris - Is the question then, well, if I compare a young newt, it would do this much better and it would do it much more faithfully than if I do this in an old newt that has done it many times.

Panagiotis - Yes. That was one of the questions. Is this an issue or not? And we proved that it is not. Actually, a newt which is very old and has regenerated repeatedly up to 19 times, the lens regeneration in that newt is almost identical structurally and morphologically and also in terms of gene expression when you do that in a young newt.

Chris - Why shouldn't it be faithfully repeated 19 years after it first happened?

Panagiotis - Well that's exactly the hypothesis that we believe that the newt would regenerate faithfully because otherwise, it wouldn't make any sense. So, we set to do this in this work - was actually started by my mentor Goro Eguchi in Japan and then we finished it to prove exactly this point. And we did prove it in the last paper, this eLife paper especially with global gene expression patterns and comparing with other tissues as well to show that the number 19 lens shows no difference whatsoever in gene expression patterns when you compare with the lens on a young animal that did not regenerate at all.

Chris - You mentioned looking at other tissues as well. So what happens? If you were to do this experiment, not with the eye but in another part of the body, do you see the same faithful regenerative effort or does the fact that it's not in an enclosed system inside the animal make a difference?

Panagiotis - We did not study regeneration of other parts, but what we did was to take the tail and also the iris from the same animals. Now the three key areas are the tail from that old animal has never regenerated. Therefore, it would be old. But the lens of the same animal has regenerated 19 times. So, what we show is that the old tail when compared with a young tail shows clear marks of ageing while the lens does not. So in a sense, it seems like keeping regenerating a tissue, it also keeps it young. It has not aged.

Chris - But that sort of flies in the face of what we understand about the Hayflick number of cells - the number of times a cell can divide before it becomes aged or senescent. Cells, if you continue to flog them into cell division eventually do give up the ghosts. So you're saying on the other hand, making them continue to divide keeps them young. So how do you reconcile your findings with what we regard as established dogma.

Panagiotis - Well, there are two ways to address this question. One is that probably, the newt has an ability to take care of senescent cells, removing them so they don't interfere with regeneration. Second is that the newt has another mechanisms that protect them in order to regenerate and to faithfully ensure that the regeneration will be taking place.

Chris - Why should these animals be endowed with this formidable regenerative ability then? They have anti-senescence mechanisms, they can regenerate tissues, and the more they regenerate, the more youthful they become. I mean, it sounds like the fountain of youth. Why should they have that? Why have they evolved to be able to do this?

Panagiotis - Well, this is a one million dollar question, even more than that. We don't really know why they do that. It is as you said, really remarkable. It's amazing that they can regenerate so many tissues, so many times at old age. Obviously, they have an amazing ability to reprogram and this is what we're trying to understand - how they do it and if it is possible to apply such mechanism in another animal. I think it's feasible but it requires a lot of work to be done and probably, we need to have an open mind on this. We need to do experiments like the one we did for 18 years that normally, people would not do.

Chris - Now obviously, when they formed a growing organism in the first place in an egg, and that turned into a lens in a young baby newt that was much smaller than the adult newt, the environment that those cells grew in was very different than the environment of the adult. So, how do those cells know the scale and stature that they need to achieve and presumably, the cell number that they need to achieve to make a much bigger body part once you're an adult that you've got to regenerate than when you were little? 

Panagiotis - Excellent question. Embryonically, the lens comes from the surface ectoderm but for regeneration, it comes from the iris. Now the iris is completely different origin embryonically. So, not only the newt has the ability to reprogram another tissue to provide the lens, but also, the numbering of cells that you said and the size, this is also an amazing property of any other animal that regenerates. They do that perfectly. So, maybe in the beginning, we start with a signal that triggers regeneration or the differentiation and regeneration. And then I think that old embryonic developmental programme takes over and differentiates the organ to the right size and the right morphology.