Lessons in Regeneration from Salamanders

(PART 3 IN OUR SERIES OF INTERVIEWS WITH RESEARCHERS INVESTIGATING NOVEL SPECIES FOR INSIGHT INTO HUMAN DISEASES)

Featuring: Jessica Whited - Assistant Professor in the Brigham Regenerative Center, BWH Department of Orthopedic Surgery and Harvard Medical School

I have always been fascinated by the regenerative potential of animals. As a junior in AP Biology in high school, I evaluated the effects of different water conditions on the regenerative potential of planaria, little worms which can regrow their heads if you cut them off.  This worked great until the opposing parts of the planaria I had dissected crawled out and over to different parts of the plate (very early lesson in failure in experimental design….).  So, I was thrilled to be connected to Jessica Whited, an Assistant Professor in the Brigham Regenerative Center and Harvard Medical School. She studies regenerative potential in axolotl salamanders, who can regrow entire limbs if lost even in adulthood. The Whited lab examines the molecular mechanisms of cellular reprogramming in these salamanders. 

The field of regenerative medicine is very much still expanding and there are many species which retain significant regenerative potential, either throughout life or in certain life stages. Broadly, regeneration has been observed in certain arthropods, annelids (worms), echinoderms (starfish, sea urchins, etc), planaria (knew that one), some reptiles who can regenerate tails, cartilagenous fish (primarily teeth, skin, scales and liver - in certain species), limited studies in birds at early ages and some species and ages of mammals.  One striking example of mammalian regeneration is the regrowth of antlers every year (almost 2cm/day!), also African Spiny Mice which can regenerate large amounts of lost skin.  

More recently at Fauna, we have been using transcriptional data from myocardial infarction studies in neonatal mammals (pigs and mice) compared with older animals to contrast with data from hibernating mammals and tease out potential pathways of regeneration that could be activated or enhanced in humans. I asked Dr. Whited to tell me more about why she chose axolotls as the focus for her research.  

What makes axolotls a key resource for biomedical research?

Axolotl limbs are structurally similar to human limbs—they have all the same tissue types—but they can be completely regenerated throughout life. Other body parts can also be regenerated. Learning how they regenerate will give us a road map for how human regeneration might one day be stimulated therapeutically in patients. 

Why did you start working in regeneration and why axolotls?

I really wanted to tackle an old and outstanding question that had been difficult to crack at a molecular level but for which new tools could be developed and used to re-examine the topic. Regeneration was ripe for exactly that when I chose my postdoc field. Since then, there has been an explosion of resources for these animals.  In my PhD studies, I also became very curious about how creatures maintained their bodies at both a cellular level, but also a larger-scale level, once they had initially developed. Salamanders seemed a natural choice for these reasons, though of course working with them was way more challenging on a logistical level than working with fruit flies. 

What is holding the field (or your research) back? 

There is a ton of momentum in the field, but additional funding and people would of course move the science forward faster. We still have a long generation time to deal with (almost one year), so more technologies for addressing gene function in the meantime, while still pursuing true genetic loss-of-function homozygous mutants, are critical.  Other resources, such as antibodies that work in axolotls and other salamanders, are also important. Genetic resources across salamanders are still developing as well. Finally, it would be great to see a commercial source of axolotls for research so that there was less of a bottleneck in operations being animal availability. 

How have you seen research axolotl and other ‘non-traditional’ species change over the last decade and where do you see the field going?  

With de novo transcriptome assembly especially, more species are becoming accessible to molecular study than ever before. We also finally now have access to a sequenced genome. 10 years ago, neither of these existed, and we were cloning genes using methods that people working in the most common genetic models rarely had to resort to.  I think the field really is driving toward understanding what are the cells critical for regeneration and what factors do they use to make it happen. Once these are more clearly defined, comparing them to mammals and possibly identifying the key differences will be important. I think it is completely possible humans have all the right “parts” to regenerate limbs—and some of them might even be activated following amputation—but these cells encounter an antagonistic (pro-scarring, anti-regenerative) environment and they also lack cues to organize into a blastema (a collection of cells necessary for regeneration). If we knew more of the nuts and bolts of this whole process, it might be possible to remove these roadblocks and also provide critical cues to the cells to coax them to come together and make a blastema. I also think the specialized, pro-regenerative wound epidermis formed in highly-regenerative animals is going to be very important. Knowing what factors if produces can give us clues of what might promote regeneration at the injury site.

Where do you see synergy between your work and that of other "non-model" organism researchers?

We all need to be willing to go full steam at a problem knowing we still have one hand tied behind our backs. New tools are coming online, but it’s still not like working in an organism where you can search a repository and order up a bunch of mutant animals for a particular take the next steps in your research. 

What do you wish people understood about axolotls?  

Axolotls hold more than just these limb regeneration secrets—we have so much more to learn from them. While I’m very grateful these lab stocks exist, they are critically endangered in the wild. It would be very sad if they go extinct, and to imagine all the other species that could offer us special insights that we might not get otherwise going extinct before they are even studied is really terrible. Working with these creatures takes time and extra effort, but it is totally worth it.