[RADIOLAB INTRO]

MELISSA WILSON: Could I ask when this might air?

MOLLY WEBSTER: Yeah.

MELISSA WILSON: I'm four months pregnant today.

MOLLY: Congratulations!

MELISSA WILSON: And I just got a—yeah, no, it's super exciting. And I was diagnosed with Hashimoto's six months ago. So it was just like ...

MOLLY: Oh. Wait. Is Hashimoto's an autoimmune disorder?

MELISSA WILSON: It is.

MOLLY: Huh!

MOLLY: I'm Molly Webster.

LULU MILLER: And I'm Lulu Miller. This is Radiolab.

MOLLY: And today, we are looking into one of the biggest medical mysteries, which is why a body sometimes turns on itself.

LULU: And Molls, you're going to lead us through this one.

MOLLY: Yeah. And it's something I got pulled into when I first was working on Gonads.

[ARCHIVE CLIP: Gonads!]

LULU: Gonads.

[ARCHIVE CLIP: (singing) Gonads. Gonads. Gonads.]

LULU: For anyone who hasn't listened is the romp through sex-freaking-ed you didn't know you didn't know. What was the actual tagline?

MOLLY: The parts of us that make more of us.

LULU: The parts of us that make more of us. That's good!

MOLLY: So gonads was all about, like, sex development, right?

LULU: Right.

MOLLY: So I was, like, deep in Xs and Ys, and when do we kind of divide off on these paths that are called, you know, gender in, like, the top-level world. And while I was in that space, one of the things that came up was that there are sex differences in how we get diseases.

LULU: Okay.

MOLLY: And one of the places this is, like, very apparent is in autoimmune disorders. It's very puzzling.

MELISSA WILSON: Why does autoimmune disease occur eight times more often in women than men?

MOLLY: Is it that big of a difference?

MELISSA WILSON: For rheumatoid arthritis it is, yeah.

MOLLY: Wow.

RHONDA VOSKUHL: And of course, in MS, it's two-thirds to three-fourths.

MONTSERRAT ANGUERA: Hashimoto's disease, 95 percent are women.

MOLLY: That's like almost the entire case study!

MONTSERRAT ANGUERA: Yeah. Isn't that crazy?

LULU: Wow.

MOLLY: So I just—I fell into this, like, series of conversations with, interestingly, like, very provocative women scientists who are, like, trying to answer this. And we're gonna circle back to each of them. But first, a little basics. In autoimmune disorders, your immune system, it starts attacking you. And there's, like, various ways it can do that. It can be anything from you have skin rashes to patchy skin to infertility to—you have neurodegenerative, like, MS, like, breaks down your brain and your nerves, so you end up having trouble walking and cognition. Some of them, you die earlier from. Some of them, you know, are just, like, an itchy patch on your skin.

LULU: Mm-hmm.

MOLLY: So it really is the gamut. And honestly, on top of all this, it seems like incidences of autoimmune disorders are going up. And so you have this real question of, like, why?

LULU: Yeah.

MOLLY: Like, what's happening here? So this has to be genetics. This has to be at the genetics. And so, Lulu Miller, we are going on a journey.

LULU: Okay.

MOLLY: Go to the bathroom now. We have three stops to get through. Starting with ...

MONTSERRAT ANGUERA: Montserrat Anguera.

MOLLY: An immunologist.

MONTSERRAT ANGUERA: And I'm at the University of Pennsylvania.

MOLLY: And her way into this mess is by looking at one of the most well-known chromosomes.

MONTSERRAT ANGUERA: I'm absolutely fascinated by the X chromosome. I love this chromosome. That sounds so silly, doesn't it? [laughs]

MOLLY: No!

MOLLY: And while we all know this chromosome for sex, Montserrat knows it for this other thing.

MONTSERRAT ANGUERA: The X chromosome has the highest density of immune-related genes of all the chromosomes.

MOLLY: Oh, my gosh!

MOLLY: And so now this is interesting because everyone on the planet has one X. But typical females have two. And so Montserrat wondered, like, could there be something going on with this extra X packed with all of these immunity genes that's leading females to get autoimmune disorders more?

MONTSERRAT ANGUERA: Exactly. Exactly.

MOLLY: Now traditional wisdom is that if you have a second X or a third or a fourth, it will get turned off or something called silenced.

MONTSERRAT ANGUERA: Fifty percent of the cells are gonna silence mom's X. The other 50 percent are going to silence dad's X.

MOLLY: And the way it does this is actually a really physical process, because wrapped around any extra X are these long strands of RNA.

MONTSERRAT ANGUERA: We can look using a microscope at the nucleus of a cell. And we can use probes that are specific for the long noncoding RNA, and we can light them up in pink. And what we see is that RNA will form this beautiful cotton candy cloud structure that completely envelops the inactive X chromosome.

MOLLY: Wow! So it's, like, muzzled.

MONTSERRAT ANGUERA: Yeah. It's like, yeah, swaddled.

MOLLY: Swaddled.

MONTSERRAT ANGUERA: It's absolutely beautiful.

MOLLY: Beautiful. And, scientists assumed, durable. The thought was that once an X was silenced and this starts in an embryo, it would stay silent.

MONTSERRAT ANGUERA: Absolutely.

MOLLY: And not just that, experiments have shown that in cells where this doesn't happen ...

MONTSERRAT ANGUERA: The cell will just start to, like, die.

MOLLY: So Montserrat was like "Okay, I'm just gonna take a look at this extra X and see what's going on."

MONTSERRAT ANGUERA: So in lupus, 85 percent of patients are women.

MOLLY: And so she looked inside cells, immune cells of people with lupus. And what she saw ...

MONTSERRAT ANGUERA: No cotton candy cloud. Instead of being the fluffy cotton candy on the inactive X chromosome, they had dispersed patterns of RNA.

MOLLY: When she looked inside, she saw little pinpoints of hot pink all over the nucleus.

LULU: Whoa.

MOLLY: So it's not muzzling. It's, like, shredded—it's like—it's just all around.

MONTSERRAT ANGUERA: Right.

MOLLY: Okay.

MOLLY: And so it's like—what does this mean? What Montserrat is thinking is that maybe this X being unsilenced is allowing extra immune genes to turn on, which is throwing the immune system into, like, this turbo charge. And that could be contributing to autoimmune disorders.

LULU: So she's saying more Xs able to unsilence means more genes firing off?

MOLLY: Yeah. Obviously, there's a ton more research to do. And this is just a working hypothesis, but there's one more piece to this which is that as she was seeing these Xs become unsilenced, she was just like, "Huh! You know what? I'm gonna poke around in the cells of healthy folks, too, in, like, their immune cells." And she found that in those cells, also X can sometimes get unsilenced.

LULU: Huh. So is that like a pre-warning sign that they might be about to get sick?

MOLLY: Not necessarily because, like, 30,000 things contribute to autoimmune disorders. But it might account for this other pretty rad sex difference you see in humans.

LULU: Okay?

MOLLY: Which is that if you just look at, like, stereotypical females and males who are healthy, on the baseline, females have stronger immune systems than males.

LULU: Okay. So you are sitting next to Soren. You're—like, you're on guard. You're ready to fight. I mean, does that then—does that reflect in those disparities? Like, do men have more, like, thing—like, I don't know, viruses?

MOLLY: Well, yeah, yeah, yeah, yeah. Well, this is why the COVID numbers are so skewed, right? The guys have three times greater likelihood of going into the ICU and they have a greater chance of dying than women.

LULU: Is that why? I mean, it's not—like, lifestyle part of it really may be a part of the puzzle might ...

MOLLY: Part of the puzzle of why is just that, like, women have stronger immune systems that do stronger initial responses and so can often fight back viruses or bacteria better.

LULU: Do people know this? Like, is this—that's so—I—that's so cool. Like, women just run ...

MOLLY: I know. This is what I'm—yeah.

LULU: ... around with better immune systems all the time?

MOLLY: On any given day, a female walking around on the street is ready to fight off a pathogen in a way that, like, men aren't.

LULU: [laughs] It's just—I'm picturing like ...

MOLLY: Yeah.

LULU: ... spears, like, pew pew pew! Like, we just got this whole army, that men are, like—like, their warriors are like ...

MOLLY: Yeah.

LULU: ... filing their toenails and like ...

MOLLY: Yeah. And you're like, this is such a crazy cool superpower.

LULU: Yeah.

MOLLY: And then I have this, like, one moment where I'm like, "I will get less flu, but I may get rheumatoid arthritis."

LULU: Right.

MOLLY: Like, so there's, like, this ...

LULU: Right. There's always the whole evolution tradeoff thing. You can't just get a gift, it seems.

MOLLY: That is true. It is very hard to be excited about the superpower if you are worried about the back end of it. I'm just gonna think about my little toxic Xs inside of me.

LULU: They're a little ticking time bomb, yeah.

MOLLY: [laughs] I don't know why I'm giggling.

LULU: So ... [laughs]

MOLLY: That just is not what I expected. It struck me as funny. Okay.

LULU: Yeah.

LULU: When Radiolab comes back, we are going to learn how the heck we got here and a possible way out.

[LISTENER: My name is Jazz Adams and I'm calling from Los Angeles. Radiolab is supported in part by the Alfred P. Sloan Foundation, enhancing public understanding of science and technology in the modern world. More information about Sloan at www.sloan.org.]

[JAD: Science reporting on Radiolab is supported by

Science Sandbox, a Simons Foundation initiative dedicated to engaging everyone with the process of science.]

LULU: Molly.

MOLLY: Yes. Lulu. Hi.

LULU: Hi. This is Radiolab. We are back from a quick break. Today, we are talking about—what are we talking about, Webster? We are talking about why it is beautiful and terrible to be a person with two or more X chromosomes.

MOLLY: Mm-hmm. Yeah.

LULU: Because on one hand, like, maybe you're a little bit better at fighting off viruses. But that same immune system can also turn on you. So I do think sometimes this just happens. There's accidents. There's imperfect innovations in evolution. But is there any sense of, like, why this might be advantageous, why this might be the case that we are the unfortunately or fortunately chosen ones?

MOLLY: Yeah. There's probably a few different ways into why, but I talked to one scientist who gave a really—I don't know, almost, like, haunting beautiful why.

LULU: Haunting and beautiful, all right.

MELISSA WILSON: Let's just circle all the way back.

MOLLY: And that's our second scientist.

MELISSA WILSON: Melissa Wilson.

MOLLY: She's a geneticist and ...

MELISSA WILSON: Professor at Arizona State University.

MOLLY: And Melissa is taking us all the way back to about a hundred million years ago to when the placenta evolved. And so as you'll remember from our last episode ...

LULU: Recently met and got to know intimately.

MOLLY: We did, so I won't go deep into it here. Y'all should go listen. It's called "Everybody's Got One." But what you need to know here ...

MELISSA WILSON: The placenta is not the DNA of the pregnant individual.

MOLLY: It's like a foreign object. And so your body naturally wants to fight off something that's not part of it. But the placenta was pretty wily, and it started doing things to essentially get the mother's body to let it stay and to not attack it.

LULU: Right.

MOLLY: And so one of the things the placenta does is it quiets the mom's immune system.

MELISSA WILSON: The placenta itself is blubbing off signals to downregulate the pregnant person's immune system.

MOLLY: And it's, like, just shushed.

MELISSA WILSON: So the pregnant person's immune system has to say, "Okay, sure. You know what? We're gonna downregulate components of that. That's fine. But you know what? If I downregulate everything, I don't have sanitation. I don't have antibiotics." This is over most of evolutionary history, if I downregulate everything ...

MOLLY: Dead.

MELISSA WILSON: ... I will die, right? And so the pregnant person's body has to do this kind of tightrope walk. It has to take those signals from the placenta to downregulate components of it. But it also needs to say, "You know what? No, I can't downregulate everything. I have to upregulate some things to be able to not die of parasites and pathogens."

MOLLY: So Melissa's hypothesis is like, while we were all co-evolving—right?—like, the human mammal and our ancestors were starting to get a placenta. And the placenta and the fetus and the human ancestor mammals were all trying to figure out how to live with each other. In this big dance, one of the things that happened was if the placenta is gonna drag down the immune system ...

LULU: Yes, right.

MOLLY: ... to shush it, then the mom is going to start evolving an immune system that's actually stronger ...

LULU: To be overexpressed?

MOLLY: Yes. Yes. so that when it's dragged down, it's not dragged down to, like, a death level; it's just dragged down to like a moderate level.

LULU: Oh, wow. Wow. Okay. So essentially, it's all the placenta's fault. Like, we double-Xs have to walk around with these amped up immune systems to just survive its presence?

MOLLY: Theoretically, yes. And you actually might be able to see this play out, really, today because in some women who have autoimmune disorders ...

MELISSA WILSON: Their symptoms will go away during pregnancy.

MOLLY: They have—like, they have symptoms, and then it just goes away?

MELISSA WILSON: People with rheumatoid arthritis who become pregnant, it's as if their autoimmune disease is gone. This also happens with MS, multiple sclerosis.

MOLLY: What does 'go away' mean like, if I—we could talk specifically about MS or rheumatoid arthritis or both?

MELISSA WILSON: The inflammation that people have in rheumatoid arthritis around their joints, around their spine, it literally disappears. For a subset of people, for a large subset of people, it's as if—it is the best possible treatment.

MOLLY: And rheumatoid arthritis—you know, for 75 percent of people, symptoms will go away. And in multiple sclerosis, it's like an 80 percent reduction in flare-ups.

LULU: Geez. I mean ...

MOLLY: And not even just a reduction in the symptoms, but in some cases, you actually get cognitive ability back.

LULU: No! No way!

MOLLY: It's huge. And so I had just, you know, these experts all telling me that, like, they have these anecdotal stories of women who just ...

LULU: Yeah, yeah.

MOLLY: ... want to be pregnant at the time because they get such relief in their symptoms or such a slowing of disease progression.

LULU: Yeah.

MOLLY: I mean, obviously, it is not a slam dunk for every individual or even every autoimmune disorder. Some of them actually get worse when you're pregnant, some say the same. Some we just have no data on and we don't know. But it does make you wonder.

MELISSA WILSON: The first OB-GYN that I met with ...

MOLLY: You'll remember Melissa at the top of the episode told us that she's pregnant and that she recently developed Hashimoto's.

MELISSA WILSON: He said, "Oh, my colleague was just telling me about this paper they read about pregnancy and how it shaped the immune function." I was like, "That's me!" [laughs]

MOLLY: And now that she sort of like, stepped into her own research in this pretty novel way, she's actually quite curious to see if pregnancy alleviates her own autoimmune symptoms.

MELISSA WILSON: And so I'm actually going to be going hopefully to get testing in the next few months to see if the antibodies that my body is making to my thyroid have actually changed during the pregnancy.

MOLLY: Okay. So there is one more part to her hypothesis, and it could offer an explanation for not only why females get autoimmune disorders more than males but why the incidence might be going up.

MELISSA WILSON: So for nearly all of human history, we didn't have contraception. And you could be pregnant for your entire reproductive career.

MOLLY: We now live in a world where, at least in Western or industrialized nations, people are getting pregnant way less.

LULU: Mm-hmm?

MOLLY: So we're not going through the cycle of having our immune system dragged down. So if it's on high all the time, maybe that in and of itself, the less pregnancies, is actually contributing to why women today are getting autoimmune disorders more than in the past.

LULU: It's like, there's just more time that you're spent turbocharged.

MOLLY: There's more time spent at 10. And then your body is just like, "I'm constantly at a 10."

LULU: Yeah.

MOLLY: "Maybe I should go do something."

MOLLY: And so we think it's like, I've got nothing to do. Let me just start eating this body.

MELISSA WILSON: Wreaking havoc.

MOLLY: Hmm. There's this weird thing where I'm like, "Oh, crap. I should get pregnant."

MELISSA WILSON: [laughs]

MOLLY: Like, it's like—oh, and it's funny because one of my colleagues was like, you know, there's already so much societal pressure on women to, you know, follow to conform. And now, like, really, biology is telling us that 'cause we're not getting pregnant, you know, we're [bleep] ourselves, essentially?

MELISSA WILSON: No, no, no.

MOLLY: Yeah.

MELISSA WILSON: No, keep going, though.

MOLLY: No but then the funny thing is then I think, like, the reverse of that is like, you know, how many kids would be enough kids?

MELISSA WILSON: Yes.

MOLLY: You know?

MELISSA WILSON: We don't know, right? We don't know yet. We don't know if it—we don't know if it's more important that you start reproduction as soon as you're reproductively active, or whether you maintain it over the whole course or is two enough, if you have one 10 years apart or—we have zero idea.

MOLLY: So Melissa was basically like, "Okay, slow your roll. First off, there's so many things that can contribute to an autoimmune disorder. I don't think this is gonna be your solution. Also, like, do you have one? Do you know you're going to get one?" Like, we don't know ...

LULU: Right, right, right.

MOLLY: ... anything about them, really.

MELISSA WILSON: Science is not saying go get pregnant. It's not, a hundred percent not. What it's saying is that pregnancy may have shaped our immune systems, so let's figure out what components of our immune systems respond to the placenta, what components of our immune systems act independently of that, and then we can narrow in on the treatments.

MOLLY: Is anyone trying to study it?

MELISSA WILSON: Absolutely, yes.

MOLLY: Okay.

RHONDA VOSKUHL: What is the factor?

MOLLY: Which brings us to ...

RHONDA VOSKUHL: Hi, my name is Dr. Rhonda Voskuhl.

MOLLY: ...Our final scientist.

RHONDA VOSKUHL: I'm a professor of neurology at UCLA.

MOLLY: So Rhonda's out there in California working to understand what specifically, precisely is happening during pregnancy. And she's narrowing in on something that's being produced by the placenta at levels the body just hasn't seen before.

RHONDA VOSKUHL: Something happens during pregnancy whereby the fetal placental unit makes a kind of a novel estrogen. And this estrogen is called estriol.

MOLLY: And that is an estrogen called estriol.

LULU: Hmm.

RHONDA VOSKUHL: Now all of a sudden, you have this burst of a new estrogen, a different estrogen. And it's at a very high level.

MOLLY: And at the end of pregnancy, your body is flooded in estriol. And the baby's body is flooded in estriol. It's like a primary hormone that just skyrockets during the third trimester.

LULU: Wow.

RHONDA VOSKUHL: And then after delivery, it drops abruptly. Well, of course, it's made by the fetal placental unit.

MOLLY: AKA the placenta, who has been manning the estriol dials, has left the building. And I could probably tell you some boring things that wouldn't actually help you understand estriol more. It's just like a different-shaped molecule than other estrogens. It has particular functions for the fetus. It could be used in neural development. It's also used by the placenta to turn down the mom's immune system. And so she starts clinical trials. And she's been doing them since, like, 2007. In 2011, she takes non-pregnant women who have MS, and she gives them estriol.

RHONDA VOSKUHL: And we showed that it reduced these enhancing lesions by over 70 percent.

MOLLY: Symptoms go away. They see disease progression slow.

LULU: Whoa!

RHONDA VOSKUHL: The other thing that's pretty cool is as we were doing these trials in humans, there was an improvement in cognition. It is neuroprotective.

MOLLY: I basically was like, "Can I get some estriol," you know?

LULU: Yeah. I mean, well, I was Google—as you've been talking, I was like, are there estriol pills?

MOLLY: So it would be a pill, except it's not approved anywhere yet for MS. In Europe, I think some people might give it off-label because it's been approved for menopause.

LULU: Just for XX ...

MOLLY: Just for ...

LULU: Okay.

MOLLY: Just for XX individuals or X-plus individuals.

LULU: And would this work? Could estriol work on a guy or an XY person?

MOLLY: That's an interesting question. I mean, theoretically yes, because it's a natural hormone. Rhonda says, like, you'd have to keep an eye out for different feminization things. Like, would it act on their breasts in a certain way. It works in XY mice.

LULU: Oh. So meaning, like, the XY mice given some estriol. And they ...

MOLLY: Yeah, they ...

LULU: Wow.

MOLLY: They saw a reduction in inflammation. Yeah, yeah, yeah. But they've not done any clinical trials on XY humans.

LULU: Okay.

RHONDA VOSKUHL: There is a strong case to be made for estriol in MS women and probably rheumatoid arthritis. I think there's a case to be made in psoriasis. There's clearly a role for a pregnancy level of estrogen as a treatment for these autoimmune diseases in women who've already got the disease. I think there's clearly a role for further investigation into that.

LULU: And also really quick, you said at the very beginning ...

MOLLY: Yeah.

LULU: ... that, like, this is the work of provocative women. Why did you use the word 'provocative?'

MOLLY: Because they're looking into stuff—like, when I talked to Montserrat, she said that, at the time, she was the only scientist in the world looking at X-inactivation in autoimmune disorder.

LULU: Really?

MOLLY: And do—that's stupid. That's like—that's insane to me. And Rhonda Voskuhl? Like, she is—the studies that she's doing, like, nobody else was doing. And Melissa's pregnancy compensation hypothesis just came out two years ago. So I used the word 'provocative' because they're asking questions and doing work that, like, nobody else is doing. And they're actually, like, upending science. Like, Montserrat's paper that showed that X-inactivation is not constant from time of embryo onwards is, like, upended.

LULU: Like, 17 textbooks had to be like, "Oh, we gotta scratch out this dogma of how it works." [laughs]

MOLLY: It's like the Earth is cracking, and they're the ones that caused the quake. Does that make sense? I don't know. I have no idea where this ends. [laughs]

LULU: Yeah. But this—it sounds like what you found is, like, this very substantial start. It's—yeah.

MOLLY: That's the thing. That's—you know Rhonda's getting paper after paper after paper that says we're seeing estriol make a difference. And then we've got this X-inactivation stuff. Then we've got this pregnancy hypothesis. And it's like, it feels like we're at the—whether we like it or not, the very beginning of a story. So there really is no ending—yet.

LULU: Hey, whatever happened to Melissa.

MOLLY: Oh, yeah! Okay, so you know how she asked when the story was going to air?

MOLLY: That was two years ago.

MOLLY: Oh, hi, baby!

MOLLY: And when I jumped on the phone with her recently ...

MELISSA WILSON: That's the 15-month-old, and the 3-month-old is sleeping.

MOLLY: ... I found out it has been quite the two years.

MELISSA WILSON: I have two pandemic babies. And one of them has gotten to be home with me 24/7 for his entire life. [laughs]

MOLLY: Well, then I'll just say—okay, so maybe you can just tell me then about the pregnancy, and what did end up happening. Because I feel like that was, like, a cliffhanger in the interview, where for months, I was like, I wonder—I don't know what her symptoms are. And if she was having symptoms, like, I wonder if they went away.

MELISSA WILSON: So any symptoms that I would have acknowledged would have been tiredness, some hair loss and getting cold. But then when you're pregnant, your hair does wonky things and ...

MOLLY: So her hair did get better when she was pregnant.

LULU: Great.

MOLLY: And she did feel less tired.

MELISSA WILSON: But ...

MOLLY: But one thing did jump out at her. Before she was pregnant, as part of her disease, her thyroid was acting really wonky.

MELISSA WILSON: Occasionally, my thyroid antibodies, which is part of the way they diagnose it, they just spike up to, like, thousands of times larger than they should be. It's just like, they give you the test. And they say, like, "Oh, the range should be, you know, single digit to double digit." And when yours is in the thousands, you're like ...

MOLLY: Wow. That's what it was, actually in the thousands?

MELISSA WILSON: Oh, yeah.

MOLLY: And then while she was pregnant ...

MELISSA WILSON: My thyroid and my thyroid antibodies and everything was just normal.

MOLLY: ... her numbers stopped spiking.

MELISSA WILSON: Yeah, yeah.

MOLLY: Did you—I remember you said to me—there are—I've talked to women who have been like, "I just wish I could stay pregnant because I feel so much better." That's not the reason for your back-to-back pregnancies. It wasn't like, "I feel so much better. I'm gonna stay pregnant."

MELISSA WILSON: [laughs] No, no. It was that we wanted a second baby. And we're—and the universe saw fit that they should be so close together.

LULU: Molly Webster. This episode was produced by Sindhu Gnanasambandan and Molly Webster.

MOLLY: And the Gonads theme song that you heard at the top of this episode was written, performed and produced by Majel Connery and Alex Overington.

LULU: Thanks for listening. Bye.

[LISTENER: Radiolab was created by Jad Abumrad and is edited by Soren Wheeler. Lulu Miller and Latif Nasser are our co-hosts. Suzie Lechtenberg is our executive producer. Dylan Keefe is our director of sound design. Our staff includes Simon Adler, Jeremy Bloom, Becca Bressler, Rachael Cusick, W. Harry Fortuna, David Gebel, Maria Paz Gutiérrez, Sindhu Gnanasambandan, Matt Kielty, Annie McEwen, Alex Neason, Sarah Qari, Arianne Wack, Pat Walters and Molly Webster. With help from Shima Oliaee, Sarah Sandbach and Candice Wang. Our fact-checkers are Diane Kelly and Emily Krieger.]

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