Heads are rolling in Nature

The Nature website has been overrun with headless flatworms, my RSS feed tells me! These adorable guys called planarians are known for their ability to regenerate from almost any little scrap of their squishy bodies. (And yes, I find lots of things adorable.) More than a century ago, TH Morgan, who invented like half of modern biology, observed that a whole planarian complete with a head, tail, eyes, brain, and digestive system can regrow itself from a fragment as tiny as 1/279th of the original animal*.

If you’re not familiar with these neat creatures, here’s one of regeneration expert Alejandro Sánchez Alvarado’s pet planarians from Wikipedia:

(OK, “pet” is probably the wrong word. Unless your concept of pets involves frequent mutilation and poisoning.)

Of course, once humanity discovered that planarians can do that, we just had to try and figure out how. Solana_etal2012-ctrlheadWho knows, one day the knowledge might even help us boost our own pathetic regeneration abilities. (Well, aside from the fact that planarian regeneration is pretty weird compared to what vertebrates do. But they are dead easy to keep and you can do lots of fancy things with them.) I felt like I should include some pictures of head regeneration in action, so here’s a few shots from Solana et al. (2012). Watch the eyes!

When you chop bits off a planarian, the remainder of the body has to know a couple of things to repair itself correctly. First, of course, it has to recognise that something is missing. This happens when tissues that don’t normally meet come into contact as the wound closes. The system can be fooled – if you cut off a piece of worm, turn it upside down, and stick it back on, things start growing out even though technically nothing is missing (Kato et al., 1999). The next step is to recognise precisely what needs to be replaced. An example of failing at this step is this two-headed flatworm obtained from a chemical treatment (from Nogi et al. [2012] via Wikipedia):

Making heads or tails

So how does a headless planarian know whether it needs a new head or tail? There’s a venerable theory (apparently also TH Morgan’s) according to which the body of the animal has a sort of built-in molecular coordinate system. Some molecules are more abundant at one end of the beast, while different molecules mark the other end. The anterior (head) and posterior (tail) signals would interact negatively, banishing each other from their respective head(or tail)quarters and resulting in opposing gradients. So any particular point along the head to tail axis would have a precise level of “headness” and “tailness”, and a wounded worm would “know” exactly where it was cut based on this information.

The tail end has long been known to be a seat of an ancient signalling pathway. Wnt (pronounced “wint”) genes are really, really important in a variety of developmental processes; in fact, it’s been proposed that they were involved in defining the head to tail axes of animals long before the more famous Hox genes (Guder et al., 2006). (The merits of that proposition are a discussion for another day. :)) Similar to their axis-defining developmental role, they – or rather, one of the several pathways they act through – also signal “tail” in adult planarians (Gurley et al., 2008).

Butts rule?

In one of the three new planarian studies, Umesono et al. (2013) set out mainly to figure out how the less well-understood head signal worked, but they managed to chuck in something vastly more interesting (to me, evolution nerd that I am) in an almost throwaway paragraph towards the end of the paper. Not all planarians have awesome regeneration superpowers. In particular, many species have difficulty regrowing heads while they can still regenerate tails just fine. Umesono et al. found out why.

Knowing how important Wnt signalling is in making tails, they wondered if an over-enthusiastic Wnt system might be behind some species’ head regeneration defects. They took members of such a species, demolished their Wnt pathway by hijacking their own gene regulatory mechanisms, and proceeded to hack off their heads. A couple of weeks later, shiny new heads started appearing!

It’s not just that one species, either. The other two new headless worm studies (Sikes and Newmark, 2013; Liu et al., 2013) basically did the exact same thing with two other kinds of regeneration-deficient planarian, and got the exact same result. So it looks like the same failure to overcome tailness underlies head regeneration failure in these three species.

The latter two papers examined worms from the same family, and the two animals proved to fail at regeneration in eerily similar ways. Everything up to a point goes correctly: the wound heals properly, stem cells across the body start dividing and gather at the amputation site… and then it stops. Wnts run rampant, heady genes remain silent, and nothing regenerates.

What I’d like to know is why it’s nothing rather than a second tail. After all, the molecular makeup of their wounded parts is screaming “tail!”, and they can regenerate missing tail ends. If you overactivate Wnt signalling in better regenerators among planarians, you still get something growing out at the front, it’s just not a very good head. (Umesono et al., in fact, did a couple of experiments like that in the process of figuring out heads.)

I thought the key was in the Umesono paper, because their prime suspect for “head stuff” as they call it is actually briefly needed in tail regeneration as well, so if it’s not activated at all due to too much Wntiness, then nothing will happen. But if you can turn that on in the middle of a tail in one species, why can’t the same thing happen in the others, which are also perfectly capable of regenerating their tails? Does tail regeneration work differently in them?

Did I mention that living things are complicated?

(And this is the part where I don’t start discussing the whole issue of how and why regeneration is lost in evolution. ‘Tis beautiful, but the night’s getting old ;))


*I can’t for the life of me find the original source, even though I distinctly remember having read Morgan’s account. The 1/279th figure is cited, among others, by Newmark and Sánchez Alvarado (2001).



Guder C et al. (2006) The Wnt code: cnidarians signal the way. Oncogene 25:7450-7460

Gurley KA et al. (2008) β-catenin defines head versus tail identity during planarian regeneration and homeostasis. Science 319:323-327

Kato K et al. (1999) The role of dorsoventral interaction in the onset of planarian regeneration. Development 126:1031-1040

Liu SY et al. (2013) Reactivating head regrowth in a regeneration-deficient planarian species. Nature advance online publication 24/07/2013, doi: 10.1038/nature12414

Newmark PA and Sánchez Alvarado A (2001) Regeneration in Planaria. In: Encyclopedia of Life Sciences. John Wiley & Sons Ltd, Chichester. http://www.els.net; doi: 10.1038/npg.els.0001097

Nogi T et al. (2009) A novel biological activity of praziquantel requiring voltage-operated Ca2+ channel β subunits: subversion of flatworm regenerative polarity. PLoS Neglected Tropical Diseases 3:e464

Sikes JM & Newmark PA (2013) Restoration of anterior regeneration in a planarian with limited regenerative ability. Nature advance online publication, 24/07/2013, doi: 10.1038/nature12403

Solana J et al. (2012) Defining the molecular profile of planarian pluripotent stem cells using a combinatorial RNA-seq, RNA interference and irradiation approach. Genome Biology 13:R19

Umesono Y et al. (2013) The molecular logic for planarian regeneration along the anterior-posterior axis. Nature advance online publication, 24/07/2013, doi: 10.1038/nature12359