Ros John: Why the placenta is the battleground between mum and dad

Ros John, Image courtesy of Ros John

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To find out more about the wonders of the placenta, I caught up with an old colleague, Professor Ros John. Ros was a postdoc in the lab of Professor Azim Surani where I did my PhD, tolerating my student idiocy and clumsiness as we tried to figure out the mysteries of genomic imprinting, where the genes that come from mum and the genes that come from dad are used differently in the developing fetus. 

Now running her own group - the Pregnancy Research Epigenetics Group or PREGLab at Cardiff University - Ros’s research focuses on understanding maternal mental health, imprinted genes and the role of the placenta during pregnancy and even beyond. And, as you’ll hear in the background, her dog decided that it wanted to get in on the interview too, sorry.

So, to start with,  what is the placenta, and what does it do?

Ros: Really good question, because I think years ago everyone thought the placenta was very boring. It's this horrible, floppy tissue that comes out after the baby's born.

Kat: It's just full of blood aargh

Ros: it's full of blood, and it just gets chucked in the bin. Well, it doesn't just get chucked in the bin, so it's checked to make sure it's intact and then it just gets chucked in the bin. But actually, now we recognise that the placenta is actually performing all these fundamentally important roles. It's not just a simple device for transporting nutrients from the mother to baby. It's actually, the bit that we specialise on, it's an endocrine organ. So it makes all these hormones that flood the mother's system during pregnancy that induce all these adaptations that are required during pregnancy.

Ros: So the example would be if you ate something very sugary, normally, when you're not pregnant, you get insulin secretion from the pancreas and all that excess glucose is sort of shuffled away into your peripherals. But in pregnancy, the baby needs nutrients to grow. And so it's really necessary to ensure that the mother, when she eats food, that some of the nutrition crosses the placenta to the baby. So one of the key adaptations of pregnancy is altering the way the mother manages glucose and other nutrients to ensure enough of that crosses the placenta.

Ros:  And it's the placenta that drives those adaptations in the mother. So you get increased peripheral insulin resistance and also increased secretion of insulin from the pancreas. So that all happens, and that's all normal in a pregnancy. And that's also why women are highly susceptible to gestational diabetes, because that's when that whole system goes wrong.

Kat: So let's dig in a little bit more into what the placenta is actually like. We can imagine the pictures like in a text book where you've got the fetus, the baby, and then you've got this big pink thing with lots of blood vessels drawn in it. So what's it made of and how is it actually constructed as it develops? Because it's a big thing that's got to grow in not a very large amount of time. It must be incredible.

Ros: It's huge. So it's about one sixth the weight of a normal baby at birth. So the mother is actually, a lot of the mother's energetic, her diet and nutrition is actually going to grow placenta as well as growing the baby. But the placenta needs to be that big in order to support this growth of the fetus.

Ros: So you've got brain development, development of the body of the fetus and the fetus is obviously expending energy during the pregnancy, as is the placenta. So it's a very sort of energetic process to support fetal and placental growth. But the placenta actually starts off very early in pregnancy. It's the very first cell lineages that's defined in a pregnancy is actually called the trophoblast, which is the lineage that then goes on to make this huge placenta.

Kat: So going right back to the very earliest stage of life, when mummy and daddy love each other very much and you've got egg and sperm come together and that fertilised egg starts dividing and you get a little ball of cells. So at what stage are some of those cells deciding, OK, we're going to do placenta, you're going to do baby. Off we go.

Ros: So it all happens pre-implantation, obviously. And so it's within a couple of days of fertilisation. You get some cells that are deciding that they're going to be trophoblast cells. It's the first decision that's made and those cells develop in a particular position, which is related to how the embryo is developing and some of those cells, as they attach to the uterine wall, will then sort of accumulate in that region where they've attached to the uterine wall, which is the uterus, which is the mother's tissue, where the baby implants and then they start to really proliferate when they implant in order to make this placenta.

Kat: It's an incredible process thinking about the growth of this, the growth of the blood vessel entwinement that needs to happen to make this all work. And one of the things when I was researching my book about cancer that was interesting was this idea that in humans, we have these genes that enable us to build a placenta and they're all involved in invasiveness and making blood vessels. And those are the kind of genes that get hijacked when cancers become invasive and start making blood vessels. And I guess this is all sort of this is a deep biological process that's deep in our evolution, but it can go kind of wrong as well.

Ros: I think that's one of the things that's actually really remarkable about the placenta, which is that first of all, half the genes in the placenta belong to dad. So it's essentially a kind of foreign body. And yet the mother doesn't reject it. So the placenta is sending these signals to the mum to say, don't reject us because we're growing a baby. And so there are cells and genes that are involved in overcoming the mother's immune system and also invading a little bit. So invading the uterus a little bit in order to then attract blood vessels and create this circulation where there can be an exchange of nutrients and exchange of hormones between mum and baby.

Ros: And so all of those genes are obviously similar to genes that might be used by cancer cells to invade the immune system and also invade tissues. But what's really remarkable about placenta is it stops. So placenta do not actually invade any more than they need to in order to support fetal growth. And you don't get bits of the placenta breaking off and going off to other parts of the body. So actually placenta is really well controlled. So it invades just enough to do its job and no more.

Kat: It's absolutely fascinating. So what do we know about what's controlling this process of placental growth and setting it up to be this complex organ that's, not only providing nutrients and oxygen, but making all these hormones and doing its thing?

Ros: Well, we know a lot about the cell types that make up a placenta, and we know a lot about using model systems. We can actually understand how stem cells develop into different cell types to have different functions. So some cell types of placenta are mainly focussed on transporting nutrients, and then some cell types are mainly focussed on making hormones. So these are the hormones that flood the mother's system to induce all these adaptations that we were discussing.

Ros: So we know a little bit about how those lineages develop, and we know up to a point how that's controlled. But there's a lot of things we don't know. So one of the really interesting things about the placenta is it's a transient organ. So it's only around in humans for nine months. So how does it know when the job is done? What is the thing that sets off the delivery of the baby? And then how does the placenta know it needs to keep going for that length of time?

Ros: There is quite a lot of interest about something called placental ageing, and one of the ideas is that some placenta may age more quickly, and that could then result in some of these complications that you see in pregnancies of fetal growth restriction being an example.

Kat: Oh right. So the timer is a bit too fast. It's like, yeah, we're cooked, but oh no you're not.

Ros: Yeah, yeah, exactly. So it's yeah, so it's ageing too quickly. And then of course, there'll be a big interest in finding out why that might be the case.

Kat: So coming back to the work that you do, we used to work together a long, long time ago in the lab trying to understand how do you make a baby? How do you go from this single egg into a fetus? And what's the interplay between the genes that come from mum, the genes that come from dad and the environment of the womb and all this kind of stuff? So what are you looking at now to understand what's going on in this process of development and this role of the placenta as this much more than an interface, but as a bag of hormones?

Ros: Yeah. So you and I, we worked together at Cambridge and it was a really fantastic time of studying these really odd genes, which are the imprinted genes and then I'd carried on with that work. And so we end up studying these genes in the placenta and what was the function? And what we found which was really, at the time, it was really remarkable and yet absolutely intuitive is that imprinted genes regulate the number of cells that make placenta hormones.

Kat: Wild.

Ros: So they're fundamentally regulating the amount of hormones the placenta makes. So this is the offspring's genes, and they're influencing the mother's adaptations to pregnancy

Kat: And not just the offspring's genes, because half of the fetuses genes are from dad.

Ros: Exactly.

Kat: Some of dad's genes operating on mum through the placenta and going, you get this, you don't get that, I want this.

Ros: 100 percent. Yeah. Yes, exactly that. So what we found, which is the big discovery that we made a few years ago, is that imprinted genes regulate the numbers cells that make hormones and that this particular gene that we've been working on, called PHLDA2 that gene has been silenced by the dads germline. And what we found that that gene does is it's a negative regulator of the number of cells that make hormones. So what dad has done, one way of thinking about it, is that dad has switched off his copy that he's giving to his offspring, and that increases the number of cells in the placenta that make hormones, so the mother is receiving a higher dose of placenta hormones.

Ros: Now, hormones are really important for nutrients, so the male genome is trying to extract higher level of nutrients for his offspring, for the offspring. And then we sort of went a bit further than that because the other thing that hormones do, which is not well recognised, is they actually act on the mother's brain.

Kat: Oh wow.

Ros: So you can imagine if I rushed into your room at 3am in the morning screaming my head off.

Kat: Oh dear god.

Ros: Covered in excrement. You'd probably not be very happy to see me, right?

Kat: No.

Ros: No, but the new mother, the new mother has to do that every single night for the first few months. So the new mother is adapted in order to take on this role of caring for her very vulnerable newborn infant. And those adaptations actually happen during the pregnancy. So the new mother is actually primed in this role. This mothering role.

Ros: And you can see this really, really clearly in rodents. So there’s loads and loads of fabulous work that's been done by many different labs showing that a rodent mother just responds straight away to her pups and she knows exactly what to do. She licks them and grooms them and makes a nice nest for them. And that virgin mothers, actually, they don't know what to do, and they have to kind of learn this behaviour of a number of days.

Kat: And what if you just have a female mouse and you give her a pup? She's like, I don't know.

Ros: Yeah, exactly, exactly. So same as I was before I had my baby. I was like, What the hell? So you kind of know, it's a thing that's primed by hormones. So what we did was, we knew that placental hormones were important for this priming of the mum's brain, and we knew that imprinted genes control the number of cells that make hormones.

Ros: And so we actually did a little experiment where we gave mother mice different types of placenta, making more or less hormones, and we could show that the mothers paid more or less attention to their pups when they were born. And yet these mothers were fully wildtype mothers. And actually if you gave them wildtype pups, they pay more attention to those pups because they'd been primed in pregnancy. So we proved that link between the placenta and the mum's brain.

Kat: This is wild, so the fetus, through the placenta, is sending messages to the female brain to get everything ready and also to get more nutrients for itself to to grow as big and strong as it can as well.

Ros: Exactly. So it's sending all these signals to the mother during the pregnancy so that the nutrients come during the pregnancy. It also stimulates the department of the breast for lactation. So it's actually ensuring nutrients after birth. And then the fetus is telling mum, I'm on my way, you need to be ready for this because it's going to be a bit of a shock when he got me to look after.

Ros: So all of this happens normally in the pregnancy, and it looks like the male genome has kind of got involved in this to influence the amount of care the mum gives her offspring. And so we kind of sold it a bit as this idea that the male genome was boosting maternal care of the offspring.

Ros: OK, my original title was actually Paternal manipulation of maternal care.

Kat: That sounds a bit creepy.

Ros: Yeah, exactly. That's what I thought. I thought hmmm this is probably not going to get past the reviewers.

Kat: Yeah.

Ros: So I went for boosting, it's a bit more positive. So it's really, really important that mothers have this adaptation in order to look after their offspring. And it's interesting to speculate that the imprinting is kind of taking advantage of this. So it comes back to this parental conflict about who does what.

Kat: And I do remember when I was doing my Ph.D. with you about genomic imprinting, and there was this idea of the conflict and imprinted genes are how males can exert some kind of influence in their offspring. Because if you think about the role of a male mammal in procreation, it's, each, shoots and leaves, if you like. And so this is some way of having a bit more influence in the developing fetus. And then ultimately the chances of success and then passing your genes on to the next generation because that's really what's all about, you know, you have to have babies and those babies have to have babies.

Ros: Exactly. So our finding was very, very consistent with this parental conflict hypothesis, which you've just described really, really well, which is this idea that both parents have a child or children. And in a mammalian pregnancy it's the mum that provides all the nutrients in utero and provides nutrients postnatally through lactation. And then we're kind of taking that a bit further and saying what is also maternal care?

Ros: It's not saying that dads don't. They're not involved. They are. So dads are involved in parental care and non-pregnant animals are involved in care. But it's the mother, the new mother that has this ready primed care and so does the big load initially. So yeah, it was quite an important finding for us and very, very entertaining at the same time.

Kat: I mean, that is something that I wanted to dig into a bit because I know a lot of this work has been done in rodents, in mice and things like that. But obviously, childcare and caring and parental roles are so heavily gendered and you perhaps run the risk of saying, well, you know, women, you're just meant to do this and go and change shitty nappies and wipe snotty noses and clean bums and things. And that's because it's just in your biology, right?

Ros: But this was the interesting thing, right? So in our little observation, this is with rodents. And so what we showed was these mothers spent more time looking after their pups and licking and grooming them and nurturing them. And they spent less time making nests. And so I mean, obviously, you need a nest. But they just were less focussed on the nest building. So you could argue that they're actually spending more time looking after their offspring and less time on housekeeping. I sometimes drop that into a conversation.

Kat: So biology says get a cleaner.

Ros: Well, exactly. Someone's got to do it and so mum's busy doing the nurturing bed. But yeah, I think in a human scenario, it's obviously very different interpretations of the roles of individuals and what people can now do, you know, in terms of parenting children. So we make decisions about what we're going to do, whereas with other mammals, you know, it's not that easy to kind of have a discussion about who's going to do what.

Kat: Yeah, there's not two lions sitting down like going, Are you going out hunting today or is it my turn?

Ros: Exactly, exactly. So we can make those kinds of decisions. And you know, obviously the extent to which our studies in rodents are really mapping onto what happens in humans, it remains to be proven. And then obviously, with human pregnancy, there's a sort of more serious side to it, which is the other bit that we ended up looking at, which is in human pregnancies. You've got something called prenatal depression. So you'll have heard of postnatal depression. Everyone knows about postnatal depression. About eight to ten percent of mothers have postnatal depression after they've had a baby. Well, it turns out that actually mothers are more likely to be depressed in pregnancy. So there's a higher rate of depression in pregnancy.

Ros: So it's quite a serious complication of pregnancy. And we've actually done some further work to have a look at some of the genes that we've been studying in an animal model to see whether their expression might be altered in the placenta of women with depression. And it looks like that might actually be the case and that most recently, we've been looking at a hormone called placental lactogen. And we've shown that placental lactogen, the expression of that hormone in the blood of women is lower in women who have postnatal depression. So some little bit of evidence that the sort of phenomenon we're looking at in animals, in an animal model, may actually have relevance to quite important complications in human pregnancy.

Kat: This feels so important because it does feel that there has been less attention focussed on researching women's health and health in pregnancy and particularly mental health when it has such massive implications for outcomes and not only mothers lives, but the lives of their children and this role of all the hormones that are going on, why are we not looking at this more?

Ros: One hundred percent Kat. You're just so spot on, actually. So there was a recent report called the RAND Report and identified pregnancy research as the least funded research in the UK compared to actually the cost of pregnancy and pregnancy complications.

Kat: It's mad, everyone's got to be born. Why don't we research it?

Ros: You know, it's something that obviously impacts all of us. We've all been born. Some of us give birth. We all know people, you know, so it's hugely important. But I think it's just not researched because it's also considered to be something that's natural. You know, it's natural to be pregnant and have a baby, and we shouldn't be interfering too much. But I think what we really know and understand is that obviously most pregnancies go well, but if a mother's depressed in pregnancy, it is linked to the baby being born a little bit lower birth weight, and it's also linked to children being at increased risk of neurodevelopmental problems and mental health problems later in their lives. So it's quite important that we actually try and understand the mechanisms that increase the risk.

Ros: Some of it will be genetic, but some of it is clearly environmental. So the other thing that we're looking at in my lab is adversity in pregnancy, because probably more than half of all pregnancies in the UK now are exposed to some sort of adversity, whether that's due to mothers having a very high fat, high sugar diet or living in a stressful situation or being a bit overweight. There are all these adversities, and we know those adversities are linked to some of these outcomes of low birth weight and problems later in life.

Ros: But we also know the same adversities are linked to increased risk of mothers having depression and anxiety in pregnancy and afterwards. So there's this huge kind of story emerging about how it is important to think about the environment where mothers are pregnant and to ensure that they have the best knowledge about how to protect themselves against adversity and how to reduce the chances of developing depression and the consequences that will have for their children.

Kat: But to go back to the placenta and the work that you're doing, what are the questions that you still really want to find out about this incredible organ and what's going on?

Ros: So one of the things about the placenta that's really useful is it has the same genome as the fetus because the fetus makes the placenta. And actually, it was quite surprising when we started this, when I talked to quite a few people and they thought the placenta was part of the mum and like, No, no, it's actually part of the fetus.

Ros: So not everyone knows that it's fetal and it has the fetal genome. And that means you could use the placenta as a tool to actually measure genes so you can look at DNA sequence, but you can also look at the expression of genes in the placenta as a sort of proxy for what maybe is happening in the fetus.

Ros: So one of the things that we're looking at with our placenta is to look at the sort of transcriptional signature of a placenta from mothers who are reporting depression versus our control mothers who have no indication of depression. To have a look at what genes might be altered, and that might give clues to why children exposed to depression are more likely develop certain disorders later in life. So that's one of the things we're really interested in.

 Ros: And then the other thing that we're very interested in is what environments in pregnancy, what exposures are actually causing the kind of changes which we're then linking to diseases. And you know this brings me back to my imprinted genes because they are epigenetically regulated. So it's a really attractive idea that these epigenetically regulated genes in the placenta are actually responding to different environments and then modulating the amount of hormones that are made by the placenta, which is then influencing the mother. And so that's the other bit.

Ros: So yes, we looked at this sort of before and after aspect of it now and then obviously looking for other genes that might also regulate placental hormone production in humans and in mice.

Kat: And one final question. When you had your daughter, did you get a good look at the placenta? Were you allowed to take it home?

Ros: No. So I don't want to go into details because I don't want to put anyone off having a baby because it's amazing having a baby. But it's a bit of a crazy bit when they're coming out. I was busy. But I do remember someone saying it was awfully big and I was thinking, you know, dads won the parental conflict thing here because, you know, big baby, big placenta. But yes, it did go through my mind, but I was mainly focussed on on the important bit of giving birth.

Kat: Yep, not quite the moment to be thinking about science. That’s Ros John from the PREGLab at Cardiff University.