This week, somewhere in the neighbourhood of 7500 biologists descend upon Washington DC for the American Society for Cell Biology. I made it here today just in time to hear a lecture given by Alejandro Sanchez Alvarado, a Howard Hughes Medical Institute Investigator at University of Utah, who’s been using the planarian Schmidtea mediterranea as a model for regeneration. His website has beautiful pictures. Planarians are regenerative heroes — long know for their ability to completely redevelop from pieces as small as 1/279th of the original. And even though they’re strange – they have a mouth that doubles as an anus that Sanchez Alvarado calls a “manus” – they are actually surprisingly complex. Thomas Hunt Morgan studied them and did a great job of characterizing their regenerative abilities, but when genetics came on the scene at the turn of the 20th century, the planarian was left behind in favour of more genetics friendly organisms like Drosophila.
But developments in the past decade have changed that. The 800 Mb genome of planaria has been sequenced, and manipulating genes is possible thanks to RNA interference. His group can shut down any gene they want just by feeding it bacteria engineered to produce short RNA strand specific to that gene. I’ve spoken with Sanchez Alvarado before, and I find his work fascinating. He talked about a number of projects he’s been exploring with the tiny worms, including investigating the properties of so-called neoblasts, a population of stem cells that exists almost everywhere in the organism and appears responsible for its regenerative prowess. A particularly interesting project, however, was a follow up from an 1898 paper written by Morgan. Morgan cut a very thin slice from the middle of a planarian and watched it regenerate. For a piece cut from the middle of the worm, normally the head end (anterior) would regenerate a head and the tail end (posterior) would regenerate a tail. Instead these slices grew into worms with two heads and no tail. Morgan called them ‘janus,’ not to be confused with the worm’s ‘manus.’ And he apparently wrote in the paper: “There is something here that is important to find an explanation for.”
Using RNA interference to tinker with genes known for their roles in setting up anterior/posterior polarity (these are genes from the Wnt pathway, which was discovered in Drosophila), Sanchez Alvarado’s group has recreated the janus worms. When they fed the worms RNA designed to block the production of beta catenin and cut the worms up, pieces from the middle grew two heads. By blocking a gene that is known to work antagonistically with beta catenin, known as APC, the group was able to produce these freakish worms with no heads – just two tails. The videos Sanchez Alvarado showed were great … the two tails battled against one another in a pushmepullyou fashion.
For folks who know their fly genetics this probably isn’t too surprising, but I’m fairly amazed at how well the pathways are conserved and that they work not only in the early development of the organism, but in the maintenance of developed organ structures and their ‘re-development’ in the regenerative program. Also, when silencing a gene very high up in the pathway, the group found they got no phenotype, which suggests that there may be another sequence of genetic events running the pathway in this instance. The E.E. Just lecture is a minority in science award to honour Sanchez Alvarado, a native of Venezuela, for his pioneering work in rejuvenating this classic model for regeneration. What a great first lecture to fall into!