Stem cells and tropical diseases

Chris -   And finally this month, human worms.  Phil Newmark and his colleague Bo Wang from the University of Illinois at Urbana-Champaign have discovered a population of stem cells in schistosomiasis bilharzia that enable the worms to repair themselves when the human immune system attacks, and to enable the parasite to massively increase its numbers by dividing asexually in aquatic snails.  As such, they represent a major therapeutic target.

Phil -   In this study, we were interested in asking how it is that these really important human parasites called schistosomes generate so many infectious stages of their life cycle.  Many parasites wind up using both, what they call a definitive host in which they can reproduce sexually, as well as an intermediate host that the life cycle also has to go through.  And so, these organisms have to be able to infect a snail.  What happens in the snail is something truly remarkable in that, a single creature that hatches out of an egg that comes from an infected human for example can enter a snail and produce thousands and thousands of the stage of the life cycle that can now swim through the water and infect humans.

Chris -   Why is that remarkable Phil, that something could produce thousands of infectious progeny like that?

Phil -   Well, it's interesting because basically, what you have is, inside the snail is one hatched creature, will go through an amazing asexual reproduction.  And so, we were interested in this asexual reproduction because the major focuses of my laboratory is to study regeneration in planarians which are a related flatworm.  These planarians are famous for their ability to regenerate.  So, a small piece of the worm can regrow an entire new animal.  Part of their regenerative abilities leaves these animals to also be able to reproduce asexually by fisioning.  So, what we were intrigued by was this asexual reproduction in the snail which appears to be driven by a similar kind of stem cell we see in planarians.  We were interested in knowing how this bag of stem cells when it enters the snail can now basically produce thousands and thousands of embryos without fertilisation.  One of the things that inspired us to start looking at this was, we published a paper earlier this year showing that the adult parasites, the adult schistosomes that reside in a human host have stem cells that are very, very similar to those that we see inside the adult planarians.

Chris -   What do the adult worms, the schistosomes in the human doing with those stem cells because they don't presumably don't serve much of the same process of the human because once it's in the human, it's then more interested in shedding eggs, isn't it?

Phil -   Yes, so what we think they're doing in the human is, these adult schistosomes can survive inside a human host for decades, during the course of that long lifespan in hospitable environment of the human bloodstream, they must be experiencing tissue damage, and they must have to replace cells that are just lost during the course of wear and tear.  And so, we think that the stem cells in the adult are serving the purpose of maintaining all of the tissues over the animal's long lifespan.

Chris -   So, how did you try and investigate further what these stem cells were doing in the snails?

Phil -   The first thing that Bo did, he found an RNA binding dye that could label these cells very nicely.  Bo was then able to measure when those cells begin to divide as the creature transitions from the outside of the snail to the inside of the snail, part of the lifecycle so he could measure when those cells begin proliferating.  He saw that over the first couple of days of this transition, there was a dramatic change in the number of these cells and how much they were dividing.  And so, what he then did was to use next generation sequencing technology so he could basically just isolate RNA from the stage before it's in the snail, and then from the stage after it's been in the snail for several days.  And there has been time for these cells to really proliferate and expand, we should find genes that are expressed in these stem cells.  And then he looks at what those genes are, he sees that they share very many similarities with the kinds of genes we see in the adult schistosome stem cells and in planarian neoblasts.

Chris -   Effectively, what we've got here is a population of stem cell-like cells that are present in the organism when it infects a snail.  This enables the organism to dramatically increase the population because it's clonally expanding inside the snail, coming out into the water so it can then hit many, many people.  But then those same stem cells endow the adult worm with a defence capability and regenerative capability against human immune attack.

Phil -   That's kind of how we're thinking about it.  We've seen these intriguing similarities.  And now, what we really would like to do is to ask exactly how these cells are propagated throughout the whole lifecycle.

Chris -   And thinking of therapeutic potential because one always has to consider - I mean, schistosome is second only to malaria probably as one of the world's worst parasitic infections and certainly the biggest disease burden.  So, if you've got this population of cells that are crucial to the behaviour of two of the key components in that lifecycle and you can single them out, do you think there's a therapeutic avenue there?

 Phil -   Yes, that's exactly right.  so, we think long term as we study these cells more and learn more about what they're doing in the context of the adult, as well as how they're required for generating the infectious portion of the lifecycle, that yes, these could be really important targets for compromising the viability of the adult worm or perhaps, preventing their propagation.  One of the intriguing things is, if these cells are very similar, maybe we can use the snail stages, the lifecycle as a way to screen for drugs that will inhibit the ability of these cells to function that will also work in the adult.