Mapping the ovaries, with Dr. Kathleen E. O’Neill

[00:00:00] There is a story. This is Dr. Kate O'Neill. Now she's a reproductive endocrinologist. But this story that she's about to tell you takes place when she was a young resident.

[00:00:16] So when I was a resident, probably about 24 25, I had already gone through my first year of training. So I'd like learned all the basic tools, I was starting to feel like a functioning physician. And I went to a community center where there's a lot of people that this is the first time they had seen a doctor, they had never seen a

[00:00:34] gynecologist. And I walk into the clinic area, I kind of have an idea sense in my mind of the things I'm going to see. Polycystic ovary syndrome, endometriosis, you know, the very common gynecologic conditions. And I actually really liked puberty and I found it very interesting. So when I see the first patient with my attending physician who was wonderful and Dr. Veronica Cross, I still remember her, you know, I went to see her, I was in the hospital. And

[00:01:07] I went and saw a 15 year old girl who was there with her mom. And you know, she had a bunch of sisters and they'd all had their periods early. And so when she's 15, she hadn't had her period, why hadn't she had her period? What was going on? And so I instantly go into like, Dr. Moat, okay, I got it delayed puberty. What are the causes of delayed puberty? It could be coming from the hypothalamus could be coming from the level of the ovary could be at the and so I started asking all of those history questions. And I'm like, Okay, there's you know, this is leading

[00:01:37] towards something structural. And I put her you know, please put your feet in the footholds and this is the first gynecologic exam she's having. So I'm trying to be, you know, sensitive to that. And I feel like we've got a good rapport. And then I tell her, okay, now let your knees fall out to the side. Everything looks as I would expect typically had already done a breast exam. She has you know, appropriate breast development for a 15 year old, she has axillary hair, she has pubic hair. So all of the things that I would expect a 15 year old have in terms of puberty or development, I look she has labia. And then I part the labia

[00:02:09] ready to do my exam. And where I would see usually an opening which is the vagina, there's just skin, nothing. I was not anticipating that I was not ready for that. I had learned about that way back like you know, a neuron is firing but I couldn't really get there and I just froze. And at that moment, looked back at Dr. Cross but okay, am I and Dr. Cross is like, Okay, great. All right. And so exam is done.

[00:02:43] Okay, go ahead and get dressed. I watched her as she counseled the patient that she had been born without a uterus that she had a condition called Meyer-Rokotanski-Kusterhauser syndrome. She was born without a uterus. This means you're not going to have periods like your friends and watching the patient kind of process that and watching mom try to support her but kind of also in her head what does this mean for me? What are we going to do? And then she said, you know, okay, I'm not going to have periods. Okay. And then how

[00:03:13] am I going to have babies? She didn't recognize that like that also meant you needed the uterus to have a baby. So at that time, we said, you know, well, you still have ovaries, you have eggs. So thank God IVF was around at that time, you could go through process and we could collect your eggs but knowing for a lot of the patients that I was seeing at this community clinic, that was never going to be affordable for them. So for all practical purposes, I was telling her she was never going to have her own children, children that were genetically related to her. And watching a 15 year old process that

[00:03:43] it was heartbreaking in many ways, but it made me realize that's what I want to do. I want to work in this area of medicine. And after that, I became obsessed with the development of the female reproductive tract and obsessed with the uterus in general.

[00:04:07] Hi, I'm Golda and this is overlooked a podcast where we bring women's health stories to life. On this episode, I'm talking to Dr. Kate O'Neill, Assistant Professor at the University of Pennsylvania. She's an infertility specialist and she's incredibly passionate about her work. I asked Kate why she does what she does. And the story you just heard was her answer to that question. In this episode, we're going to talk about the ovaries for an organ that is responsible for so much that it's hard to believe that the ovaries are going to be the cause of the ovary. So let's get started.

[00:04:39] It's incredible to me how little we know about it. Kate O'Neill wants to change that. Hi, Kate. Hi, Golda. How are you?

[00:04:49] I'm good. Right. Let me actually you know, this show is going to be big on storytelling. So let me tell you a little story of how I found you, which is kind of a fun story. Tell me.

[00:04:59] So I was doing some research on the ovaries and I thought, right, what does the internet have to tell me about the ovaries?

[00:05:07] And I came across this National Institutes of Health page with this title, Anatomic Nomenclature and Three-dimensional Regional Model of the Human Ovary Call for a New Paradigm. And you know what, Kate, you had me at call for a new paradigm. Good. That was the intent. I like it.

[00:05:28] So tell me for the uninitiated, tell me like in one sentence what that means, what you're trying to do. I would say first of all, for the title, I have to give the entire group credit because it really was a we workshopped that title quite a bit.

[00:05:44] So I cannot take credit alone. But we are a collective of experts in the ovary in various ways, in looking at the ovary through radiologic images, looking at the ovary underneath the microscope, looking at it clinically, looking at it in terms of research.

[00:06:03] And we all came together and said, you know, we're trying to study and describe the ovary in multiple ways. And we don't have the terms. The ovary is described really in such crude terms. It's this pole, this pole, one layer and another layer.

[00:06:21] And so it's really hard when you start doing very, very specific research to describe where you are studying which part of the ovary you're studying or clinically, which part of the ovary

[00:06:33] you are having to remove for assist or for fertility preservation or what are these things. So we said we all need to speak the same language and we all need a more specific language to describe the ovary.

[00:06:46] So that's how this group came together and we really addressed that call with that paper. Tell me the origin story of how all of this came to you and your team. Like, where did this moment of wait? Why don't we even have this language come from?

[00:07:04] So I am a part of the NIH Common Fund's Human Molecular Bio Atlas program or HubMap. And my co-principal investigators and Young Kim together, our charge is to build a 3D spatially resolved molecular map

[00:07:23] of the normal female reproductive tract in the non pregnant state. It's a mouthful. Basically what we're trying to do. I always describe it to my friends and even some of my non gynecologic colleagues as like, you can imagine Google Earth.

[00:07:39] You have Google Earth and you can see the earth and then you zoom in on North America and then you zoom in on my home state of Michigan.

[00:07:46] And then you zoom in even further on my hometown of Grosse Pointe and then even further to my house. And then you can actually see my dad's car parked in there.

[00:07:56] So you can go down to that level. What they're trying to do is the same thing for the human body. So you see the human body and then you can zoom in on the ovary. Then you can zoom in on the various tissue layers of the ovary.

[00:08:08] Then you can zoom into the cells that make up those tissue layers and even a layer further, you can say these are the proteins that are expressed in those specific cells. These are the genes that we're seeing. These are the RNA messengers that we're seeing in that cell.

[00:08:22] And it provides an incredible resource for individuals to use. It's open access so everyone will have access to this data and then they can compare disease states to normal.

[00:08:39] And that's really important because thankfully we're not taking normal ovaries out of women. We're not taking normal uteri out of women. And we don't have that baseline to study. So you can get a lot of disease tissue such as cancer, you're taking it out of the time.

[00:08:53] But you need that normal to compare it to. And so that was the goal of the HUBMAC program and specifically for me, the female reproductive tract.

[00:09:01] And as I'm taking these ovaries from these very generous deceased donors and as I'm taking this tissue, which we're very grateful for, I'm realizing I don't have a way to describe what I'm actually profiling here.

[00:09:15] So I needed a better way. And I started reaching out to people like, okay, I know there's the hilum and there's the cortex and the medulla. But like, how can I get more specific? And people were saying there is no more specific. That's it.

[00:09:27] And so that's kind of where I started reaching out to people and people started talking to people and we were like, we should all get together and talk about this with a multidisciplinary group.

[00:09:37] Because sometimes some of the things I would say is, oh, why don't we describe it in this way? And the surgeon next to me would say, that's just not possible. We don't get to that level.

[00:09:46] Or I say that and the radiologist would say, you have that level of detail when you're looking in the operating room, but I don't have that level of detail when I'm looking at an image that I'm seeing on the screen. So we all needed to work together to come up with something that was more specific and also feasible.

[00:10:01] So this is a really stunning thing to me because I'm like, wait, it is 2024. And I'm hearing someone in your position saying that we describe the ovary in really crude terms and we don't have a specific language.

[00:10:19] And I don't know, it's just one of those things that I was like, I guess we're not anywhere near as far ahead as I thought. And of course, lots of other thoughts come to me about sort of why the ovary as opposed to any other organ and we'll get into all of that. But can you give me an example? Can you bring that to life for me when you say all we've got is this non-specific language to describe the ovary? Say a little bit more about what that means.

[00:10:43] Yeah, so you know, the ovary is an ovoid structure in the uterus, usually about two to three centimeters and in reproductive age women. And when it has been described in anatomic texts, they talk about one side of it, the side of it that's being closest to the fallopian tube, and the opposite pole of it. So there's the hilum of the ovary and then there's the other side.

[00:11:05] And then when we talk about it, you know, it has many, many layers like an onion. And we describe the outside as the cortex and the inside as the medulla. And that's it. That's basically how they referred to the ovary before. We needed more specific language so we could even start to put into context some of the studies that had already been done. But we can't we can't study that if we don't have these terms available.

[00:11:29] So I'm going to ask you a really simple question. No doubt it has a complicated answer, take it anywhere you want to go with it. But why are we in this position that we don't have this level of detail? We don't have the specific language, we don't have these ways to describe it.

[00:11:45] I have a couple of reasons. The non-cynical part of me says, well, we haven't had this, the technology has developed at a very rapid pace. And we haven't had the need to describe every single cell and be able to map an organ. So technology has developed now that we can and so now we need those terms. But the non-cynical part of me says, well, we still have more specific terms for other organs.

[00:12:13] So I think the fact that only 51% of the population has ovaries, and that 51% of the population has not always been making the decisions about nomenclature are probably contributing to it. But I do think part of the reason is because the technology has developed and now we can describe things at a single cell. So now that you can describe things that specifically you need to give better coordinates.

[00:12:43] That's a very eloquent answer, I have to say.

[00:12:49] I would have gone like because we're women. Okay, so tell me so two questions really. The first is a timeline. Tell me when you started on this work and where you are right now. And then I want to ask you a little bit more about we know the work ahead for you.

[00:13:05] Yes, my team started on this back in would have been four years ago. So it's really 2020. I thought I knew everything about the female reproductive tract. But we spent a year really learning, getting the tissue, learning how to process the tissue reaching out to lots of people have been incredibly, incredibly generous, not only through hub map, there's a community through hub map where we share a lot of information, but also outside of hub map just reaching out to people and saying, you know, when you're processing ovaries, how do you

[00:13:35] do it so that you keep all of the structures intact. And so we spent a year really just figuring out how to process the tissue, what kind of studies we wanted to do on it, which were most informative, what were other groups doing so that we could kind of combine all of this data together. Because if you have all of this data about the female reproductive tract, and you have completely different information and data about the heart, how are you going to do some of those very interesting comparisons to see is a ciliated epithelial cell that is in the heart? How is it different than

[00:14:05] a ciliated epithelial cell in the fallopian tube? Those are interesting questions. We want to ask those. But if you have totally different tests that you've done on those two organ systems, you're not going to be able to do them. So we spent about a year doing that. And then we spent a year collecting tissue from actual donors, which was you're trying to get tissue from healthy donors. So you have to define what a healthy donor is, you have to, we worked really closely with the gift of life and their coordinators identifying those donors and approaching their families and asking for

[00:14:35] information, and then procuring the tissue, storing the tissue and optimizing a lot of the studies that we were doing. It's not as simple as you'd like it to be like a cookbook, like step one, you know, take the ovary, step two, put it in a tube, step three, here's all of the RNA that comes out of that piece. But it's a lot, it's a lot more work than that. So we spent a year doing that. And then we spent the third and now what is the fourth year creating all of the data, my entire life is about delayed gratification, and all aspects.

[00:15:05] And this project is completely delayed gratification, because it was three years of really working on what we're going to do and how we're going to do it. And now we're finally producing the data. And that's very exciting.

[00:15:19] No, that's great. Delayed gratification. I like the way that you describe it there. Let me ask you, did you receive at any point in this timeline? Did you receive any pushback?

[00:15:28] I did receive pushback. I received pushback with people saying, who cares? Why do we care about this? Both on the clinical side and on the basic side, people saying, we don't need to know that much about the ovary. And I think that's very interesting because how can you know what you don't need to know when you don't have the information? But I got a lot of that. I got a lot of nobody's ever going to use this. I got a lot of people are so

[00:15:58] different, that if you study eight to 10 people, which is what we were studying out to do, if you study eight to 10 people, is that really going to give you any meaningful data? So those are some of the questions and some of the pushback that I got.

[00:16:10] I would love to take that on right just for for the skeptics or for maybe people who don't fully understand the importance of the work that you're doing. How do you answer those critics? So we don't need to know much about the ovary. How do you answer that?

[00:16:24] The ovary contains eggs, which are half of the cells that are necessary to generate life. I cannot think of a more important organ to know. And I don't know why everyone wouldn't want to know absolutely everything you can about that tissue, because literally life will not continue without it. So I don't even really know how to address it because really without the ovaries,

[00:16:54] and the cells within them, you will not have future generations.

[00:16:59] I mean, yes, you won't get an argument for me on that. And then you know, the second thing you said of being asked, nobody's ever going to use this, I kind of look at that question in the other way. And you know, I'd love to hear more about how this will be used once we have this information, what is going to change. But I also have like, a

[00:17:19] momentary sense of loss of all the things in science that haven't happened, because we haven't had this already. Right? And, you know, of course, there's a long and complicated history in medicine with women's bodies. But if we had this 10 years ago, 50 years ago, 100 years ago, if our information that we gathered and the knowledge that we knew about the ovaries matched that of the heart, for example, what could we have done before? How

[00:17:48] many lives could we have saved? What could we have changed? Is my reaction when I hear you say that just a sense of like, my God, it's taken us so long to get here. And it's great that we hear so let's push forward. But the sense of looking back, but before I get too morose about about it, you know, push this forward for me, tell me what you hope will change now that we're starting to gather this data, this what seems like very like basic foundational data.

[00:18:15] Yeah, I think part of it is in order to study and understand disease, you have to understand normal first. And it's not sexy. It's not that fun. People would rather study the disease tissue, it comes out. So it's really it's easier to study. But until you know normal, you can't even identify disease, especially early disease, right? Because early disease doesn't necessarily need to come out. And so I think when we want to start

[00:18:45] in medicine in general, we want early detection, we want less invasive diagnostic tests looking for things that are in the circulation, early markers. And I think the only way you can identify abnormal is when you know normal. And there's still so much about the ovary and and my other favorite organs, you know, the uterus and the fallopian tubes, I don't want to leave them out either. But there is so much that we have left to know about normal. People aren't taking normal ovaries out of women nor should they.

[00:19:15] And so you end up with only getting pieces of normal ovaries from somebody who's probably having surgery otherwise, so it's not completely normal. Or it's you know, very small piece because it's a willing volunteer, something like that. So I think having this resource is incredibly you have the ovary in its entirety to be able to study down to the cellular level. I think that is going to be very worthwhile for some future research.

[00:19:39] So this is a podcast called overlooked. I think it's clear what's been overlooked in this conversation. But I want to ask all my guests on this show, a very broad question and you can interpret it in any way you want to but the question is, how is this inequality felt most deeply?

[00:20:19] I have two places. So when I was an OBGYN resident, I would see patients with ovarian cancer.

[00:20:26] Patients like your mom. And unfortunately, or luckily for you, most of the patients that I would see were at very, very advanced stages of cancer. And we know that with very advanced ovarian cancer, the mortality rates are very high. And I would take care of these patients and they would be so sick before this would get detected.

[00:20:50] And just personally, I have an aunt right now who has advanced ovarian cancer. And the same thing happened to her. You know, she was so sick up until the point where she was looking pregnant until people said something's going on here, what's going on here?

[00:21:05] It just amazes me still to this day, that we don't have better early detection for women with ovarian cancer. So I think that if we had done some of these studies earlier and knew what normal looked like, we have a lot of abnormal to compare it with. I think if we had done that, we might be farther along there. If we had won a little bit more funding in that area of research, I wouldn't say a little bit.

[00:21:34] I'm being too polite. If we had a lot more funding towards women's health, I think we would be farther along there. And if we had done some of this early work and funded the early work, it's not I'm not the first person who was wanted to do it. People have wanted to study normal ovary for a very long time. There just hasn't been there hasn't been the interest. I really applaud the NIH. We weren't in the first round of funding. The female reproductive tract was not one of the first organ systems that was covered, but it was in the second round. So I give them a lot of credit for that.

[00:22:02] So I think in ovarian cancer and in the other patient population that I really think about is the patient population. I was just talking about that. I treat infertility patients, so I see patients come in a lot of times that are in their late thirties, but sometimes that are in their early twenties. And they say, you know, started my periods have started spacing out a little bit. I want to figure out what's going on. And then, you know, through a series of tests, we diagnose them with primary ovarian insufficiency. I wish that I had more tools in the armamentarium to do that.

[00:22:32] I do have things like donor egg adoption. I'm really happy that those options exist. My mom was adopted, so I appreciate adoption and all the routes to parenthood. But a lot of people want children that are genetically related to them. And I wish that I had better tools.

[00:22:48] You know, talk about overlooked infertility is seen as an inconvenience. It is not seen as a medical condition. And I think that's a lot of where this comes from. People say, oh, they can't have that 26 year old can't have kids on her own. Well, you know, she can adopt a baby like, you know, it's fine. It's no big deal. I don't think people really realize the impact that that has. People want to know what is going on in my body. So if I don't have the words to describe it, I don't think I can do it.

[00:23:19] You know, pictures say a thousand words. But like, I can say this part here, which we don't have a name for. I mean, that makes you feel very foolish to patients.

[00:23:27] Yeah, I guess I thought it was somebody else's job to do it. And then I talked to someone like you. I'm like, what? What? What? I mean, we have no way to describe this. Like if you guys don't have a way to describe it, then what is going on?

[00:23:42] It's funny that you say it's like, it's not your job. I'm like, I know it's my job. It's my job. And it's not for lack of effort. You know, I want to study and my patients say that too. Like, well, what do you mean we don't have any treatment? Like how do we not know why this happens?

[00:23:56] And, and I want to say it's not because we don't care. It's not because we're not interested or we don't have any ideas on how to do it. It really does get down to the fact that it is not a priority for the institutions that fund it. That just has been an uphill battle every single step of the way.

[00:24:16] So I think you're right. Conversation is the way to, it's the first way because it's not like you're just going to go and demand money. That's not going to happen. But I think conversation is the way to open people's eyes to the fact that that's where the barrier is right now. The barrier isn't like we don't have the technology or we don't have the people who are willing to do the work. It's that there's that missing piece which is the support for it.

[00:24:39] Yeah. And I think now that people are aware, I think the support will come right because you know my whole, my whole Instagram feed is full of like women's health this, that and the other. But the thing that this show does is as much as possible to take it down to a granular level of the individual experience. Right? And then somebody else can collate all of that data together but nobody is gathering these individual stories.

[00:25:07] So that's so that's what I wanted to do with this. Well, I love it. Kate, thank you so much. It's been an absolutely fascinating conversation and I so appreciate you sharing all of this with me. Golda, thank you for having me. Thank you for shining the light on this and thank you for all of the experiences you shared about you and your mom and your sister in season one.

[00:25:26] We're building a community around women's health so that no one is overlooked. If you'd like to be part of it, hit the follow button on this podcast wherever you're listening to this or head to overlookedpod.com to find out more. Overlooked is written and produced by me Golda Arthur. Jessica Martinez-Eos is the show's associate producer. You can get in touch with the show by emailing overlookedpodcast23 at gmail.com. Thanks for listening.