In praise of the placenta
The stem cells in an early embryo decide whether they’re going to form the embryo itself, or play a supporting role in the placenta and other extra-embryonic tissues. Most developmental biologists focus on the embryo as it grows into a foetus - after all, that’s what becomes a baby once it’s born, so that’s super-interesting - right?
But most cases of pregnancy loss and pre-term birth are caused by problems with the placenta rather than the developing fetus. Yet, as Kat Arney discovered when she talked to Myriam Hemberger at the Babraham Institute, this vital organ has been tragically ignored.
Myriam - Placenta is still often discarded as useless and people don’t really appreciate the importance of the placenta on embryonic development.
So, we were involved in this big phenotyping screen where we had many mouse mutants that were only selected for phenotype that the embryos didn’t survive throughout pregnancy. We looked at the placentas of all of these mutant mouse lines and find that there is 70% of these lines that have placental defects.
What we don’t know is whether the placental defect causes the embryonic lethality but there's a good chance that at least in some cases it will, so it’s still a very overlooked area and that’s what we’re interested in.
Kat - So everyone has just been focusing on the embryo, the baby, because that’s going to be the animal and this wonderful structure that feeds it, that nurtures it, that grows with it just gets chucked in the bin.
Myriam - That’s precisely correct - at least often. Not always, but very often. Too often, I would say!
Kat - So tell me a bit about the placenta. What is it like? What is in there? Because I think I've just had this idea that it is just like a blob of blood and tubes.
Myriam - It does appear like a blob of tubes and blood but this is I guess its function and reflecting its function because you really have the placenta flooded with maternal blood. But then the nutrients and the gases are taken up through those placental so-called trophoblast cells and then go into the foetal circulation, and that is ultimately what feeds the baby, and what makes the baby grow, survive, develop properly.
So if you have a placenta that is insufficient, you have for example babies that are born too small for their age or are just even throughout the entire pregnancy trajectory too small or in the worse cases, won't make it at all and will die during pregnancy. And that’s the same in mice as well as in humans.
Kat - When you started studying these mice that couldn’t make placentas properly, what did you start to find?
Myriam - We started our study by really selecting which embryos don’t make it throughout their gestational period and then went backwards and looked at their placentas to try to establish at least principle cause-effect relationships.
And genetically speaking, genes weren’t selected for anything other than they cause embryonic lethality. So, it was actually a very unbiased approach which is nice because we can now go back to this list of genes and we have over a hundred that we screen very carefully.
This is something we’re doing now - we really go through the genes that we have established to cause a placental deficiency and try to see which generic and general pathways impact on placental development through these factors.
Kat - You're saying that you found a lot of mutations that meant that the embryos died, they didn’t develop properly. Had those genetic mutations formally been thought to be a problem with the embryo and you're saying, “Actually, hang on – you just chucked away the placenta. This is actually a problem with the placenta, not with the development of the foetus.”
Because as a developmental biologist, so many genes, you think, they're embryonic lethal, they lead to no development of the embryo. But these are actually placental problems.
Myriam - That is exactly right and while we cannot obviously prove this in each and every case of such a big screen, this would be correct for – I would think – quite a significant number of instances.
Even historically, there have been a handful of genes where this has been shown. So for example, very prominent exams are the c-Myc proto-oncogene as well as the RB tumour-suppressor, and they have been published already some 20 years ago as causing very specific embryonic phenotypes and defect in the brain and in the heart.
And then some years later, somebody made a genetic rescue experiment where you can, in mice, make the placenta right but the embryo still carries a mutation. And miraculously, the embryos were almost fine so that those were really their first highlight examples that actually that placenta can directly influence embryonic development. And we find that it can specifically influence heart and brain development profoundly.
We don’t know how precisely whether this is through the establishment of blood flow or through shared gene regulatory networks, but it’s definitely the case that in at least, some instances, you will be able to rescue those profound embryonic defects solely with a normal placenta.
Kat - So, if you're thinking about some of the problems that humans have with forming placentas and the number of pregnancies that are lost because of a failed placenta, potentially could this be a way to rescue pregnancies when something is going wrong?
Myriam - That is obviously a long shot and we can't really say that at the moment. But there is that prospect yes, because the benefit of the system so to speak is that the placental cells are only there during pregnancy. So you can envisage that you can manipulate them without impacting the genetic constitution of the embryo itself.
So as long as you can make the trophoblast cells which are these cells that make the placenta functional, that’s all we need. So yeah, there is that long shot prospect but we can't really address that question right now.
Kat - It must seem a bit frustrating that so many of these problems are to do with the placenta, but everyone has just been focused on the embryo.
Myriam - That is at times frustrating. At the same time, it’s a great area for us to be in. So there’s lots of work to be done. People can flood into the field because literally, so much work still to be done from the work I just described with this screen of mouse mutants that has really revealed how little we know about the genetic requirements of placentation. So yeah, we have to learn a lot still on that.
Kat - As well as the mouse mutants that you're working through to find out how these genes affect the growth of their placenta, what other aspects are you looking at?
Myriam - So, in other study that we have just finished is a study where we looked at pregnancy in older females and again, we use the mouse as a model to recapitulate some of the same problems that older women have. They also become more frequent and the woman is more at risk of them as she gets older. So usually, what we call in science ‘advanced maternal age’ unfortunately starts at 35.
Kat – An old crone in your mid-30s!
Myriam - Exactly. So women over 35 but certainly, over 40 do have a higher risk of a whole spectrum of pregnancy complications that actually have nothing to do with the egg per se.
Kat – Ooh your ovaries. It’s like how old are your ovaries and things?
Myriam - That is correct and I guess the same thing about egg freezing and people are obsessed about freezing their eggs when they're younger, in their early 20s perhaps, or even late 20s, early 30s. But what hasn’t really been looked at is that age also impacts on the rest of the woman unfortunately as we could expect.
What we have shown in mice is that when you take embryos from an old female and transplant them into a young female, they actually develop just fine. So, all of these developmental problems can be rescued at least in mice through the context of the younger mother and not to do with the younger oocyte.
What we traced this back to is actually that the uterus undergoes changes as female mice age and the uterine cells are not quite as responsive to the pregnancy hormones so they don’t differentiate as quickly and properly as they should, which means that even that embryo comes and wants to implant, they are not quite as ready to support the embryo.
And whether or not this is the same in humans, we don’t know yet. There will be certainly profound differences because the reproductive cycle in mice and humans is quite different. But it really was meant as a study to lead us into molecular pathways, genetic pathways where we can look in women and see whether they're actually affected as well. Because it is the fact that things like pre-eclampsia and pre-term birth do become more frequent in older women, irrespective of chromosomal defects.
Kat - Myriam Hemberger from the Babraham Institute in Cambridge.