Courtney Hanna: How to make a placenta

Image courtesy of Courtney Hanna

"Click here to listen to the full podcast episode"

Kat: And finally, I also caught up with Courtney Hanna, a group leader at the Centre for Trophoblast Research at the University of Cambridge. She’s fascinated not by how to make a baby, but how to make the vital organ that sustains it: the placenta. As we explored with Ros John and Sam Behjati back in episode 20 of season 4, Baby Boom, the placenta is an extraordinary tissue that is very poorly understood for something that has such an essential role in reproduction - a view that Courtney also agrees with.

Courtney: So I think it's quite interesting. We know quite a lot about how cell identity is specified or may be initiated in the embryo. This is really because it's been the predominant focus of the stem cell field and trying to research and understand gene regulation and how one lineage is specified from another and so on and so on. 

Courtney: I think we know comparatively little about how this is done in the placenta and actually I think it's so underexplored, we might not even know all of the cell types that are in a placenta. I think we've heard from many different researchers that it's incredibly complex because you have both foetal and maternal cells. So really this is unique amongst organs in that you have two individuals contributing to a single organ. 

Kat: I was amazed, one of the speakers this afternoon was saying, "you think your favourite organ is complicated, that's nothing on the placenta." You've got all these different cell types and all these different things. It's also developing and changing and genes are being turned on and genes are being turned off. What are some of the things that you are exploring, particularly with these aspects of gene regulation? 

Courtney: So we're reapproaching some of the early models that have been described in the field and going back and looking at how a specific enzyme can mark the genome, so that we know a gene needs to be turned on later in development. Or for example, maybe a set of genes that needs to be repressed throughout development.

Courtney: Then we're trying to evaluate that when you're missing this enzyme, do we fail to get these genes appropriately turned on? And does this actually implicate what cell types we can get in a mature placenta? So this is the approach we're taking at the moment to try to hone in on the really key developmental processes that are important for this.

Kat: We're talking here about this concept of gene regulation and epigenetic regulation, which we have talked a little bit about in previous podcasts, and the idea that you get these little marks, almost like post-it notes put on the genes and these little methylation marks. So what are you finding when you start to play around with the enzymes that put these marks on and off? 

Courtney: So we're just starting really. We have a model that sort of sets an active mark at genes that need to be turned on later in development. This model was described previously as having a very strong embryonic phenotype, so it fails to appropriately turn on the right genes in the right cell types, and so you don't get proper patterning of the embryo.

Courtney: But actually when we've gone back to this and looked at how the placenta is doing, it barely forms a placenta. So it seems like the cells can't even start to differentiate into the right thing. This may actually result in a very early lethality in this model, which perhaps if the placenta was rescued we would be able to progress further into development. This is just one example, but we think that it looks like this enzyme's absolutely critical in the placenta. 

Kat: So you've talked about a model. What is this? What's the system that you've set up to study this phenomenon? 

Courtney: We generate these mouse models which are missing some of these key enzymes. An example of this is a DNA methyltransferase, which establishes a repressive mark onto DNA itself and allows genes to be silenced. It's been widely reported to be important and it's widely studied actually in human pregnancy. 

Courtney: There are hundreds of studies that have looked at DNA methylation in a human placenta for association with various pregnancy complications. I think one of the challenges in interpreting these studies is we don't know whether these changes that we see in methylation in a human placenta actually might implicate or alter gene expression. So we're hoping these basic research questions in this mouse model system can shed some light on that. 

Kat: With this knowledge, understanding that this enzyme's important and studying the processes that you are, what can we start to do with this knowledge? 

Courtney: Our hope is that studies and mouse models will hone in on particular pathways that we think are maybe particularly sensitive to changes in a methylation state. Some of these post-its, if they're not laid down quite right, they may be particularly sensitive to becoming regulated in the wrong way. This will give us candidates to go look at in humans to potentially link to some of the environmental exposures or stressors or complications that are seen in pregnancy.

Kat: What are some of the questions you still want to find out? It sounds like we hardly know anything really about the placenta! What's the next thing that you really want to know?

Courtney:  There's quite a dogma in the field that because the placenta's such a short-lived organ, it's not really regulated in the same way as you would an organ in the embryo. So there's some thoughts in the field that maybe gene regulation doesn't need to be as tightly controlled. I guess I would argue maybe it needs to be controlled in an even more fine-tuned way because it has such an important role and plays the role of so many organs during pregnancy. So really to demonstrate that epigenetics and gene regulation is critical in placental development and that this is a really important area to study.

Kat: It's like the most important time of your life! If you don't have a placenta, if you don't have your connection to your mother, it's not going to work. 

Courtney: Yeah, exactly!

Kat: Courtney Hanna, and thanks to my other guests Dave Grattan and Rachel Freathy and also to the meeting organisers Ros John and Marika Charalambous, and of course to The Genetics Society for the opportunity to attend.