Shawn Luttrell: Getting a Head with Regeneration

Figure 1. Ptychodera flava, a hemichordate
 from Honolulu, Hawaii
.
“In the X-Men franchise, popular character Wolverine has sharp titanium claws, keen animal-senses, and rapid healing powers. These healing powers instantly repair broken limbs, gunshot wounds, and even help him survive a nuclear bomb blast. Now, scientists are trying to unlock the mutant’s healing powers for everyone – using the DNA of a humble worm.” – The Daily Mail 

Regenerating missing and damaged tissue may seem like it’s straight out of science fiction, but this superpower is completely real and quite common in the animal kingdom. Just as the fictional character Wolverine can heal nearly every wound, some real, living animals can not only heal wounds, but many can even regrow missing appendages and organs and multiple lineages can regenerate an entirely new animal from just a small piece of tissue. If you cut sponges, planarian worms, and hydra into pieces, they will regrow complete and normal animals from most, if not all, of the pieces. Nearly every major animal group has members that are able to regenerate to some degree. It is likely that the common ancestor of all animals was able to regenerate and this remarkable characteristic has been highly conserved in many lineages.

Figure 2. Deuterostome phylogeny. Humans are
 vertebrates, to the right. Hemichordates are a
sister group to the well known echinoderms. 
Arguably, one of the most impressive regenerating animals is Ptychodera flava. This animal, also known as a hemichordate or acorn worm, is able to regenerate every body part. All acorn worms are marine animals that have a tripartite body plan with an anterior proboscis that they use for digging in the sand and mud, a middle collar region, and a long posterior trunk (Figure 1). Why is this animal exceptional when so many other animals also undergo whole body regeneration? For starters, P. flava is a deuterostome, in the same group of animals as chordates, which includes humans (Figure 2).  Furthermore, P. flava shares numerous developmental and morphological traits with the chordates, including a hollow, dorsal neural tube in the collar region. Our lab has shown this structure develops in a very similar fashion to the chordate neural tube. In humans, the neural tube becomes the brain and spinal cord. Ptychodera flava is able to regenerate this structure de novo (anew) after complete ablation.

Millions of people suffer from neurodegenerative diseases, spinal cord injuries, and limb amputations. Furthermore, aging and age related diseases affect every person on the planet.  Regeneration may slow the aging process and regenerative stem cells present feasible ways to combat a multitude of diseases and injuries. If regeneration is a conserved ancestral trait, it is likely that humans possess many, if not all, of the genetic switches controlling regeneration, but those switches have been modified or inactivated in some way over evolutionary time. It may therefore be possible to re-activate those pathways in humans using genetic models made from animals with extensive regenerative capabilities. Understanding the morphological and genetic mechanisms for regeneration in P. flava may yield clues to unlocking more extensive neural regeneration in humans.

Figure 3. Ptychodera flava collection sites.
A) Tetiaroa, French Polynesia. B) Paiko Bay, Honolulu, Hawaii. 
To help reveal the genetic pathways controlling regeneration in P. flava, we collaborated with Dr. Alejandro Sánchez Alvarado of the Stowers Institute for Medical Research to sequence, assemble, and analyze the regeneration transcriptome of P. flava. This shows all of the genes that are being turned on and off during regeneration. For this project, we collected P. flava from Paiko Bay in Honolulu, Hawaii or on the atoll of Tetiaroa, French Polynesia (Figure 3). I bisected healthy animals in the trunk region (Figure 4) and let the posterior piece regenerate (Figure 5). I extracted tissue from the regeneration site at nine different time points and isolated RNA, which we used for our transcriptome. This work was recently published in Developmental Dynamics (DOI: 10.1002/DVDY.24457) and covered by numerous local, national, and international news groups, including the Daily Mail (above) and the Huffington Post.

Figure 4. Bisected Ptychodera flava. The boxed area
indicates the regeneration site of the
 posterior half of the animal. 
Figure 5. Regenerating Ptychodera flava. 
A) The open wound of the cut site on day zero of regeneration.
B) Day 1 of regeneration showing the wound has healed.
C) Day 7 of regeneration showing the proboscis and partial collar.
 D) Day 14 of regeneration showing complete proboscis
and collar regeneration. 
 





















Our publication details hundreds of up and down regulated genes, as well as the associated morphological events. With this data, we can directly compare regeneration to early development to determine if and how the regeneration program differs from embryonic development. Our data shows that hemichordate regeneration employs some pathways that are not invoked during early development. There is extensive temporal plasticity during regeneration, as well as different modes of acquiring the same anterior structures. This result is exciting because it means there are multiple ways to achieve the same biological structure and demonstrates developmental plasticity during regeneration. We are currently using this data to make probes to study expression patterns of neural genes during regeneration. We are also working to determine whether regenerative cells are originating from bona fide (real) stem cells or whether existing somatic cells are taking on new fates in the regenerating tissue.

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