What does it mean to be a regenerative organism? Well, unlike simple healing that happens when you get a paper cut, and new skin forms, regeneration involves the formation of multiple tissues and complex shapes. Your first reaction to regeneration may be to think of something like in Hercules when he fights the Hydra monster that upon having its head amputated immediately grows two more. When found in nature not fiction, regeneration is much more practical and perhaps less exciting – a way to replace important missing structures. Some animals, like salamanders, can actually regenerate limbs and tails and there are documented cases where children regenerate the tip of their finger.
The champion of regeneration, however, is the planarian flatworm. This 1-2mm size worm has a distinct appearance with two adorable googly eyes, and can be found swimming in the swamp muck of your local lake. After amputation of their head, they can grow back their brain, eyes, and head perfectly – no problem! The same is true for much of their entire body; they can fully regenerate from a piece even about 1/200th of the total worm. That’s quite a party trick. What is incredible is that this small piece has all the information to make the entire worm – something that doesn’t seem to be true for most mammals. And regeneration, even of just a limb, has a lot of steps. Let’s break it down. First the structures that are missing have to be identified – for a human arm, we need five fingers, a forearm, an elbow, and an upper arm. Then the missing components to building a limb have to be remade, including bone, muscle, cartilage, and skin. Finally, they all have to be in the right places to make a proper limb.
But if you look at the level of the cells, this is a pretty difficult thing to solve, because each cell needs instructions with a much finer grain of detail – whether to divide, migrate, or die in order to make a new limb. There could even be multiple sets of actions for the cells that lead to the same end goal of a correctly patterned limb. This is called an inverse problem because there is more than one way to solve the problem, and we can’t tell from the end product what set of instructions were used. It means that the information passed between cells is crucial to perfectly creating missing anatomy. In fact, in planaria, interrupting cell-cell communication has shown to have some pretty crazy effects. Some examples of the amazing morphological plasticity of planaria are that in one commonly studied species, D. japonica, interrupting the communication between cells during regeneration leads the worms to grow double-heads. In another species, G. dorotocephala, interrupting this communication between cells in regenerating worms leads them to regenerate head that look like other closely related species of flatworm! So it has been suggested that in planaria some system must be in place such that cells have a ‘workflow’ to communicate what needs to be done (i.e. to grow a head), coordinate between themselves, and report back to check on progress. This would explain how it is relatively easy to redirect this system at the level of instructions (rather than the cues to individual cells) to end up with double-headed or pseudo-species worms. This also could explain the incredible development plasticity of some other organisms. One example is that frogs with craniofacial abnormalities can rearrange these early organs during development, recovering proper facial structure. The potential that comes with the idea of “top-down” development and regeneration is that if we can find some of the master regulators, we can cue the development of structures, because we may never have the ability to direct every cell, but if we can take over the manager position with our own agenda, we could begin to control development with much greater finesse than is currently possible.
The new Allen Discovery Center at Tufts University will be a new research effort focusing on reading and writing the morphogenetic code, to find and use the top-down controls of the body. The incredible morphological plasticity of planaria will be central model organism to study, toward the center’s goal of understanding how cell-cell communication can be co-opted for large scale organ and tissue in development and regeneration. Look forward to our upcoming profile on the director of the center, Professor Michael Levin, and learn more about the research efforts of the Levin lab here.