What triggers labor?: Conversation with Dr. Polina Lishko, Part 2

The how and when of uterine contractions--how are uterine contractions initiated? Whats the trigger or triggers? And when it happens too early, why does it happen too early?  are questions we haven't been able to answer as of yet.  

Or maybe more accurately, we have a bunch of different possible answers, but we don't know how they interact with one another. 

Today I finish my conversation with Dr. Polina Lishko, who shares some of her research on a key mechanism for this trigger, and the other puzzles she and her team have been able to solve by understanding how this particular trigger works.

Transcript

Paulette: How are uterine contractions initiated? What's the trigger or triggers? And when it happens too early, why does it happen too early? Our questions we haven't been able to answer as of yet. Or maybe more accurately. We have a bunch of different possible answers, but we don't know how they interact with one another.

Today I finished my conversation with Dr. Polina Lisko, who shares some of her research on a key mechanism for this trigger she also shares the other puzzles she and her team have been able to solve by understanding how this particular trigger works. Welcome to making sense of pregnancy.

This show is a new pregnancy reference. I'm finding and talking with experts doing cutting edge work to better understand what we do and don't know about pregnancy and what you can do to better understand your own experience. Each week I'll be talking to scientists, doctors, and researchers who are trying to uncover the many mysteries that still exist in [00:01:00] reproduction, giving you the most current evidence-based way.

To approach this enormous transition in your life, I hope it'll become your go-to source for how to make your pregnancy better. Please enjoy the second half of my conversation with Dr. Polina Lishko. To start, I'll remind you of where we left the conversation last week. We talked about how there has historically been this puzzle, progesterone drops and other placental mammals. And that drop is thought to be a significant trigger for labor given that progesterone keeps the uterine muscle cells quiet. It keeps them from contracting. But in women, progesterone doesn't drop before contractions start the hormone situation has been described as functional withdrawal of progesterone, so it doesn't actually drop, but something is happening to it that makes your body think it's not as high. Dr. KO's lab has uncovered how functional withdrawal works through an estrogen blockade of the ion channel KIR 7.1, which allows the voltage in uterine muscle [00:02:00] cells to become less negative and allows those cells to fire.

At the end of the episode, Dr. Lisko was talking about how studies that test the value of progesterone to limit preterm labor. Lump everyone with preterm labor in the same group and test for the benefit of the drug. Progesterone, which is a test, progesterone is bound to fail since there are many different routes to preterm labor.

But for the group of women who experience some drop in their progesterone, her work explains why it's an issue and how we could go about addressing it, and this is how she suggested we address it.

Dr. Lishko: A simple test as probably hormonal test is to take some blood draw and look at the progesterone level would be already very helpful because in humans, progesterones produced by placenta and of course it doesn't produce enough, it'll show up, , in a simple blood test.

And those cohort of, , pregnant patient would benefit perhaps from. Well, unfortunately, FDA a pulled from [00:03:00] the market in February, , 

Paulette: it's a little surprising to me that you just group all the preterm labor people together. Since you know that there are all these different paths to preterm labor, that's some silver bullet you're looking for.

That could turn 'em all off. Right? That's, yeah. 

Dr. Lishko: Yeah. It's, it's sad is right now, except for progesterone, there's no intervention. 

Paulette: Yeah. 

Dr. Lishko: And this huge amount of, population which essentially underserved. There there's no available effective treatment. 

Paulette: Yes. 

Dr. Lishko: Yeah. And , another interesting thing, along the same, the same logic going back , to the channel.

, So because we saw this. Clear, regulation of the channel by progesterone and antagonizing of this effect by estrogen. So we thought about, okay, what about other synthetic steroids, , which are messing up function of the uterus, right? So we tested mifepristone ,RU486, uh, abor Deficient drug, right?

Paulette: Yeah. 

Dr. Lishko: Which is [00:04:00] known to give to women to initiate a contraction of the uterus, to basically to cause, uh, miscarriage. An abortion. So what we show that at the concentration, at the high concentration, 50 micromoles of this compound mifeprestone, which is exactly what would be in, human circulation if they take this, , pill, , that actually access estrogens, antagonizing effect of progesterone it blocks.

Oh, 

Paulette: wow. Yeah. It's the same pathway. 

Dr. Lishko: Yeah. It, it's the same pathway. It may explain how exactly works. So it basically causes construction of the uterus by removing KIR7.1, from the, from the table. 

Paulette: That's sort of amazing. Will you, give us a sense of the. , Ion channel landscape. So you, you've identified one specific potassium channel.

What, what were our choices? Are there hundreds? This already feels like a needle in a haystack. 

Dr. Lishko: No, no, no. , So [00:05:00] the Iron Channel landscape of the uterus is very well described. , Fortunately there are many excellent groups working in this area, including Sara England lab and many others.

And, one of the main iron channel, which is absolutely crucial for. Uterus contraction, and actually for any smooth muscle contraction, whether it's a uterus, gut bladder, it's a calcium I channel. It's iron channel, which brings calcium in. And this iron channel is also known as voltage gated calcium channel, which means it's only open when there is a certain voltage, certain positive charge, right?

So as long as you bring enough positive charge to the uterus. You can open the calcium channel, the calcium will go in and that will cause contraction. So potasium channels set to antagonize calcium channels because potasium channels bring negative charge. KIR7.1, one is one of [00:06:00] them, but there's also , so-called BK, a big conductance potassium channel.

And there's also voltage gated potasium channels and small conductors, potasium channels. But they're all kind of. They cover their range of potentials. They activate certain set of membrane, potentials and the other type activate another set. So they, there is five or six types and they cover the whole range.

So ki from one is at the, , farther, I would say left side covering the range of resting state and what the job for. KIR7 0.1 is to keep uterus as negatively as possible. 

Paulette: , It's interesting that they're specialized at different thresholds. Yeah, but that's what it sounds like. It like it, it becomes a certain level of negative and then a different channel opens and it becomes a certain level, and then.

Let me try to restate this more clearly. Uterine smooth muscle [00:07:00] cells express a handful of different kinds of ion channels that collectively fine tune how responsive the muscle is to stimulus. So some respond to hormones like cure 7.1 and some respond to voltage changes, how negative or positive the inside of the cell is.

Why do we have multiple ion channels with varying sensitivities, we have them to allow the uterus to adapt to changing demands of pregnancy and labor, so the hormone sensitive channels respond over longer periods of time as hormones change in pregnancy, and they can keep the uterus quiet when they keep the uterus quiet during pregnancy.

And the voltage gated channels can respond more quickly during labor.

Paulette: yeah, that's, the system 

Dr. Lishko: tries to keep redundancy, to, to work. But this is a very far left side, of the voltage threshold is maintained by Ki Point one in the pregnant uterus. 

Paulette: Oh. So I was just gonna ask that if you're not pregnant, you don't have these channels or what does that mean? 

Dr. Lishko: Yeah, so you don't have the [00:08:00] same, at least that's what we showed in mice.

So, non-pregnant uterus has, has minimal expression of KIR7.1. But as the pregnancy progresses, especially as the third trimester, this channel will express high. So its expression goes on with the pregnancy and maintains the high level at the third trimester. 

Paulette: Yeah, that's kind of amazing. The other thing you found in mice is that the channels are, concentrated around the implantation site.

Dr. Lishko: Yes. That's another thing. So because initially, , it was kind of a funny. Story how we, , how we, solve this whole thing. , So we knew the channel is important for the uterine contraction because of the previous work in this field. Well, what people didn't know how this channel is regulated, and also it was not known when exactly it is expressed.

So we kind of assumed, and the field assumed this channel should be there at all time. And we spent almost a year. Trying to find [00:09:00] this channel functionally recording from the uterus of non-pregnant mice or, at the early stage. And we were failing. We didn't see anything and we were at the point of depression.

So maybe as the whole thing is not correct, maybe this channel doesn't play any role until we get into this right stage at the late, late, late stage of pregnancy in mice is like a short trimester in humans. And then where we saw this huge expression of Iron channel, it's a whole regulation. That's when it become all together.

So it's, it's on a very low level in non-pregnant uterus, but it goes high and especially peaks excess third trimester. And then it also expressed exactly so. When you look at the, , rodent uterus, so mice have many pups, right? They sometimes have nine, 10, you know, and, , when you look at the pregnant uterus, there's multiple [00:10:00] implantation sites because there are multiple fetes.

So when we look at the uterus between fetes, we didn't see this channel, but this channel is highly expressed around, , around the plantation side. So basically it controls. Con contractions of the uterus exactly where, , the fetus attaches, where the fetal suck attaches 

Paulette: place. So that is super cool. But I'm wondering since, to me that makes sense in a person because the placenta is sending out all the progesterone.

But I thought you said in mice it's the ovaries and not the placenta, but it's all close enough that. That makes sense. It's smaller 

Dr. Lishko: now. Okay. So in mice it's mice are much smaller. Yeah. So everything is very close, convenient. 

Paulette: Conveniently located near the Aries 

Dr. Lishko: located. So that's not a big issue. But other thing, which is also very interesting that , and kind of serendipitously, uh, when we were looking at the [00:11:00] expression of this channel.

Usually is the way it's done in the lab. When you take a tissue, you have to suction it, you have to slice it multiple slices to look at the, , level of your target in, in those slices, right? And when we made the slices through the uterus accidentally, , we ended up in placental layer. We didn't intended to, but just kind of happened.

And when we looked at where is the channel present for us, it was shocking to find that. Another very highly expressed, , organ versus channel lights up is placenta. So it's in the uterus, in the smooth muscle, but it also happens to be present in a specific subset of cells in the placenta. They're called pericytes, and those cells control, , blood redistribution between maternal and fetal [00:12:00] circulation.

So they're kind of like smooth muscle cells, but then not exactly have the same lineage, but they behave like one and they surround blood capillary. They kind of like interrupt them and they can contract. Same as smooth muscles, right? And when they contract, they squeeze blood vessel, they cause its constriction and the less blood can be delivered when they relax.

There is normal circulation going on. So what we found that this protein in this channel is expressed in a specific part of placenta called labyrinth That's where main interface between maternal fetal circulation happens, and that's where a lot of blood exchange between fetus and mother. That channel controls level of the blood of nutrients, which will be delivered back and forth and [00:13:00] blood will be delivered with nutrients and, , byproducts will be, , sent back to maternal circulation.

So, , that was very important because that may explain partially why, , mutation as a channel. Like in mice. , So mice don't, , if it make global knockout, if it removes the cell entirely from the rodent body, they, , it's, it's lethal They die shortly after birth or shortly before the doors.

Those mice, it might be related to the inability to receive enough oxygen or enough blood during gestational development. 

Paulette: Do we know if, those KIR sites are in a human placenta? 

Dr. Lishko: Yes. That's also what we show in this paper, that human placenta expresses KIR in placenta. 

Paulette: So is that, could that be a target for, , like gestational hypertension or something like that, or no?

Yeah. 

Dr. Lishko: That's what we think may be, , preeclampsia, uh, potential treatment [00:14:00] for preeclampsia could be developed based on targeting the side channel. Because human placenta holds roughly 700, 800 milliliters of blood. That's a huge amount. That's almost one fifths of our whole body circulation. Yeah. And if the contraction of the spiral artery happens, it's a huge amount of blood goes into material circulation, leaving, fetus, hypoxic, , and if it's the same mechanism.

That may, explain , why progesterone is so important to keep normal circulation going on, and actually those cells, , which express KIR7.1, , pericytes. Right? , It has been shown in humans that insufficiency, the pericyte insufficiency is directly related to a preeclampsia. 

Paulette: I mean, it's. It's an amazing skeleton key for all these [00:15:00] problems in pregnancy.

What do you think, what do you think the future holds? Now that we understand this about KIR7.1, what should we do differently? 

Dr. Lishko: Well, I think more sure is needed to precisely understand how our own body, how steroid hormone regulates, right? Because so far people just brush it off and, , I mean, generally.

Studies in female health, particularly pregnancy and not receiving as much attention as they need to be. If you look at the field such as cancer, biology, neuroscience, right? It's very highly, , well known, highly recognized field, very important field, but they receive majority of attention when it comes to female health.

It's somewhere kind of, in the, at the backyard of the sites. It's not what people think is important, shockingly, because come on, we, we all came to [00:16:00] this world through the same way. Right? And 

Paulette: I mean, it, it's bonkers for a million reasons and, absolutely has to be changed. But also, I would imagine, and, and maybe I'm wrong about this, but that the placenta predates cancer.

Even though they share a lot of absolutely qualities, right? They have a lot of things in common. So ostensibly, you'd learn a lot about cancer if you knew more about the placenta 

Okay. Just to give a sense of the similarity between the placenta and cancer, they behave similarly for placental cells in the mother and for cancer cells, in whatever person is unlucky enough to get cancer. Placental cells multiply, move around and invade maternal tissues to establish the placenta.

These are all processes that look like what tumor cells do in the host's body that they develop in. Placental cells, remodel host tissue. Specifically, they remodel the maternal arteries to make them work with the placenta, and that's what tumor cells do.

They remodel their [00:17:00] hosts. , Tissues. Both placental cells and tumor cells use all kinds of tricks to avoid the host immune system, and some of them are very similar. Some of those tricks both pregnancy and cancer, create metabolic changes in the host, like altering, uh, glucose and lipid metabolism to support their own rapid cell growth and survival.

By no means is this list exhaustive, but this is just to give you a sense of the kinds of similarities that exist.

Dr. Lishko: And the fact people, , who work in placenta, , research field, they even, they even more ostracized, , I would say from the general science because they consider to be a very specialized field.

And, um, and the whole kind of structure of the. Science and making Korean science based on , whether you can publish in high profile journal, right? Yeah. 'cause if you can publish in high profile journal, you'll get, , better grants. You establish your lab, you move up to the career letter and so on and so on.

Right? So, so those high profile journals, they keep the [00:18:00] gatekeepers. Or science success and development, , of the field. And that also means that the field would benefit from young generation, talented people because they would go into the field where they can publish faster and establish their career faster.

So it's kind of, you know, this, ,

I wouldn't say pathological, but this is a normal cycle of sense, right? So what makes. For this high profile journals. Right. What makes interactive, , story is when the story will be highly cited 

Paulette: Yeah. 

Dr. Lishko: By other researchers, which means if the field is large, it'll be highly cited just because 

Paulette: Yeah.

Dr. Lishko: And more thousand people work in this field, but if the field is small, it'll be poorly ci just because there like only, let's say a thousand people, not a hundred thousand working in the field. So that essentially cube. , Reproductive research, reproductive biology in a smaller field and prevents its development.

This, this whole strange cycle. 

Paulette: Yeah. The, this, it's [00:19:00] a time for, cross pollinization is a Exactly, 

Dr. Lishko: exactly. So, yeah. So , if people recognize how importantly productive research is, it'll, it's like, you know, immunology, immunology used to be a smaller field, and now everyone. , Understands how important this field is in many regards, and this field is regarded as much as cancer and neuroscience Right now.

I think reproductive biology has bright future and it just based on what people recognize importance and translational impact, applicational impact and basic science impact. 

So when, , when you know the Sky Profile Journal, stop sending back our manuscript, rejected manuscript and telling us this specialized field, it has to be published in some kind of, you know, low impact journal.

Then when situation happened with this paper, it's very interesting story, right? We try to submit it to all high profile, to [00:20:00] nature to science. To, , PNS cell. We got rejected from all of this. Eventually we went to science advances and we got rejected from science advances, all the desk rejection. I mean, which in the data just thought it was specialized type.

, So we got death rejection from cell science, nature, and so science and that, and then. Six months after. , I received email from Science Advances that, we are making this special issue on female health. Do you have any manuscript by any chance? Like, guys, we just send you a manuscript. Rejected. And that's how we, I said, oops.

Oh, okay. 

Paulette: Yeah, I mean, it is, it is nuts that it's a special. It's gotta be a special section on female reproduction since it's critical to everything. But, hopefully 

Dr. Lishko: thank they're doing this. 

Paulette: Yeah. Yeah. Hopefully changes on the [00:21:00] frontier. 

Dr. Lishko: Yeah. 

Paulette: , I find it just mind blowing that you have found this needle in this haystack and a potential.

Amazing inroad into preterm birth and preeclampsia and gestational hypertension. And I should mention, you know, preterm birth is one in 10 in the US it's a super common problem. And the reason that the mortality rate in the US is much higher than you would expect for how much money and technology are here is this high preterm birth rate.

So. Being able to understand why birth is initiated and what all the triggers are, seems critical for, you know, our health going forward. 

Dr. Lishko: Absolutely. I agree with you a hundred percent. And unfortunately, it's on the rise. It's already high. , The preterm , labor rates are high and the, the horizon. We definitely need more resource.

We definitely need more, , intervention in this area. Yeah. 

Paulette: Well, thank you so much for coming on and [00:22:00] sharing your amazing work with us today. 

Dr. Lishko: Thank you so much for that. So, , I'm really, really grateful for this invitation 

 Thanks again to Dr. Lisko for taking the time to walk us through some of her work. I'm totally inspired by the persistence required to identify the timing of the KIR channels. In particular, her team's ability to uncover the fact that these important channels are essentially not expressed in real numbers until you need them.

This seems like more evidence for the idea that the uterus is a Swiss Army knife able to come up with the tool it needs for all its many complicated jobs. So inspired by this effort and finding. And at the same time, I'm so frustrated to hear that top journals consider research on female reproduction, a specialized topic.

It's almost like these journal editors forgot that one women make up half the population. So by numbers alone, this should not be considered specialized. We've run the experiment where we [00:23:00] pretend that women and men are biologically the same for the last a hundred some odd years since we've had pharmaceuticals and it hasn't really worked and.

Two. All these adaptations that the body has to make to make reproduction possible may hold the keys for many other health issues. As I mentioned, the placenta and cancer share a bunch of similarities. Might we learn both about fetal development, which affects everyone and cancer if we focus more research effort on the placenta?

Okay, official end of the rant for today. Thanks for listening. If you like the show, please share it with friends. We'll be back next week with more amazing research.