A Surprising Cause Of Endometriosis Could Lead To Cure

Since the age of nine or ten, Katie Burns https://med.uc.edu/depart/eh/directory/entire-directory/Index/Pubs/burns2ki has had debilitating pain from endometriosis, a condition where tissue resembling the uterine lining grows outside the uterus. For years, Katie was in the dark about what was causing her pain. Even after a diagnosis at age 20 it was hard to find relief, or even answers about her condition. Her search for better care is part of what led her to a career studying the disease, which affects tens of millions of people worldwide. And in 2012, she discovered something new about its origins. Today, we talk to Katie and science reporter Meredith Wadman https://www.science.org/content/author/meredith-wadman about that discovery, which points to a surprising culprit of endometriosis — the immune system. Read Meredith’s full piece in Science Magazine HERE https://www.science.org/content/article/driven-pain-endometriosis-scientist-uncovering-clues-its-causes. Interested in more health science ? Email us your question at [email protected] mailto:[email protected]. Listen to every episode of Short Wave sponsor-free and support our work at NPR by signing up for Short Wave+ at plus.npr.org/shortwave http://plus.npr.org/shortwave. See pcm.adswizz.com https://pcm.adswizz.com for information about our collection and use of personal data for sponsorship and to manage your podcast sponsorship preferences. NPR Privacy Policy https://www.npr.org/about-npr/179878450/privacy-policy

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• 0:17Regina Barber?

  You're listening to Short Wave from NPR. When Katie Burns was a kid, she remembers being sicker than her brother and sister.

• 0:27Speaker 02

  More colds, more sinus infections, more ear infections than my brother and sister.

• 0:32Regina Barber?

  Then the abdominal pain started when she was around 10. It was so bad she went to the emergency room, thinking it was appendicitis. But the doctors ruled that out.

• 0:42Speaker 02

  And they sent me home. And then I remember from there on, having more and more pain. But it wasn't really till I started menstruating that kind of my whole world was just completely shifted upside down.

• 0:57Regina Barber?

  Katie has endometriosis, a disease where the tissue that lines the inside of the uterus grows outside of the uterus, often causing debilitating pain and fertility issues. Because of her pain, Katie avoided making friends for fear of having to cancel plans.

• 1:14Speaker 02

  I didn't live, I don't think, as a normal teenager.

• 1:20Regina Barber?

  Growing up, the adults around Katie told her the pain was normal, that they were growing pains, and to ignore it.

• 1:27Speaker 02

  You would get your period and it would hurt, and you move on with life. And that's what I did. I don't know if they understood the magnitude of the pain.

• 1:37Regina Barber?

  Katie wouldn't get an endometriosis diagnosis until she was 20. A diagnosis was validating, but it didn't provide relief. To manage the pain and exhaustion, she would take naps during the week and sleep through the weekend. She tried acupuncture, diet changes, even hypnosis. One outlet that helped distract Katie from the pain was studying, which led her to a research career. Eventually, she decided to study endometriosis. As she published her findings, science reporter Meredith Wadman took notice.

• 2:10Speaker 03

  I found Katie because this force of nature named Linda Griffith, who's at MIT and develops endometriosis organoids.

• 2:20Speaker 03

  Put me on to Katie's work that was quite new and exciting and said, "This is worth looking at."

• 2:26Regina Barber?

  That new and exciting work revolved around the origins of endometriosis. Previous thinking pointed to hormones as the root cause of the disease. But Katie's work was pointing in a different direction. The first clue was that hormone treatments in people with endometriosis didn't always work.

• 2:43Speaker 02

  You can quiet disease, but you don't cure it. You don't get rid of it.

• 2:48Regina Barber?

  Then an experiment in my showed a completely unexpected result.

• 2:52Speaker 02

  I tried to convince myself that I did something wrong. The data wasn't making sense.

• 2:57Regina Barber?

  Katie did the experiment over and over again and kept getting the same results.

• 3:02Speaker 02

  It really showed that the immune system seems to be that important starting piece and not the hormone receptors.

• 3:09Regina Barber?

  Today on the show, science journalist Meredith Wadman tells us how researchers are piecing together the surprising origins of a disease that affects millions of people worldwide and how it could lead to a simple, noninvasive test, better treatments, and perhaps, one day, a cure. I'm Regina Barber, and you're listening to Shore Wave, the science podcast from NPR.

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• 5:03Regina Barber?

  So Meredith, before Katie and other scientists like her began looking into the immune system as a potential culprit for this disease, what was the main theory as to why researchers thought people were getting endometriosis?

• 5:17Speaker 03

  Well, there have been theories about the cause of the disease dating back literally hundreds of years. The most prominent, and still the leading one, is that something called retrograde menstruation is leading to endometriosis in the people who get it. Most menstrual blood goes out, as it should, down through the cervix and out the vagina. But some of it refluxes. It goes back up the fallopian tubes, which are open-ended. They open into the pelvic cavity. And believe it or not, 90% of women have some degree of menstrual blood going back out into the pelvic cavity.

• 5:58Speaker 03

  Now, why 90% of women don't get endometriosis? That's the question that people are pursuing, in essence, by trying to get to the root causes of the disease. And it's really well established that estrogen, secreted by the ovaries as a normal reproductive hormone, kind of supercharges this tissue that's growing where it shouldn't be and resists the calming effects of another key reproductive hormone made by the ovaries, which is progesterone. So it's definitely driven or not calmed by these reproductive hormones. But... We all have them and everyone doesn't have endometriosis.

• 6:41Regina Barber?

  This is really fascinating. Research now is turning to the immune system. Like, in your article in Science Magazine, you write about a study that Katie did that she had kind of this lightbulb moment that she started connecting the immune system to endometriosis. Like, can you tell me about that study?

• 7:02Speaker 03

  Well, let me preface this by saying, at the time, estrogen, estrogen was the name of the game for many decades as the driver of endometriosis, as the cause. But at this point in time, which was kind of in the aughts, Katie did this experiment where the mice she developed were deprived of estrogen. Their ovaries were removed and they were engineered not to have key estrogen receptors. And at the same time, the mouse donors, whose uteruses were sliced up and injected, also lacked estrogen receptors.

• 7:39Speaker 03

  And what she found was that even in the absence of this estrogen influence, the absence of receptors, the absence of almost any internally generated estrogen, these mice developed rudimentary endometriosis lesions. They weren't very healthy, they didn't thrive, they didn't grow, but they were there. And they were getting established. And that was the lightbulb moment for Katie, where she said, something is helping these get established that does not have to do with estrogen.

• 8:14Regina Barber?

  Yeah. And how did she get to the point where that something was related to the immune system?

• 8:20Speaker 03

  Well, she went on to do further experiments in which she actually watched what happened in these recipient mice in the, like, earliest hours, 24 to 48 hours, after

• 8:36Speaker 03

  The minced uterine tissue was injected. And she found that the peritoneal cavity, the pelvic cavity essentially was flooded with these innate immune cells called neutrophils and macrophages that were on the scene. And she proposed out of this, a model that said, it's these cells that are needed to get these errant deposits of endometrioma-like tissue growing where it shouldn't be. And then, only after about 72 hours, is estrogen absolutely required and becoming the primary actor.

• 9:15Regina Barber?

  So since then, have other scientists kind of connected the dots between endometriosis and the immune system?

• 9:22Speaker 03

  Oh, yes, there have been ranks and ranks of scientists, often unsung, probing the role of the immune system in endometriosis.

• 9:33Regina Barber?

  Yeah, what are some of the things they found?

• 9:35Speaker 03

  Yes, they have found a lot, and even more, since that 2012 paper by Katie Burns. They have found that natural killer cells that should be targeting and removing and zapping this misplaced tissue are few in number, and they're not putting out the cell-killing substances they should be. They found that neutrophils are hanging around the scene and getting old and being inflammatory instead of quick zooming in and doing their hoovering up function and disappearing. And they found that macrophages, which are another early player at the scene of tissue turning up where it shouldn't be, are really helping the tissue launch and nurturing it

• 10:20Speaker 03

  as it gets embedded in places it shouldn't be, instead of vacuuming it up and removing it. And genetics is clearly a piece of all of this. Probably about 50% of endometriosis is down to genetics, but it's not simple and straightforward, like there being an endometriosis gene.

• 10:40Regina Barber?

  So what does this mean for, like, treatment? If the immune system is the culprit, like, given that a lot of endometriosis, like you said, focuses on estrogen therapies, what could be a different treatment?

• 10:55Speaker 03

  Right, so this is, you know, what's really promising and yet virtually almost entirely unrealized is that the immune system could present targets for drugs that would be more effective. And endometriosis in one woman or person is not the same as in another, like it's more complicated. And so what a drug that works for one person might not work for another. But basically, the immune system could allow, for instance, antibodies manufactured to attack a particular inflammatory product of the immune system, a so-called cytokine.

• 11:39Speaker 03

  These antibodies could target these cytokines and basically calm everything down, stop the inflammation that is driving the pain in these people. And there are other approaches, like a team at the University of Edinburgh that is just about to launch a human study of a drug called nibrosatone. And it goes after macrophages. I shouldn't say goes after. It improves their ability to clean up cells that are growing where they shouldn't be.

• 12:13Regina Barber?

  So Meredith, researchers have also started collecting menstrual fluid to try and understand endometriosis. What have they learned so far from that?

• 12:22Speaker 03

  Oh, they're learning a lot. And really hats off to this group at the Feinstein Institutes for Medical Research on Long Island, who pioneered this more than 10 years ago and were getting laughed at, you know? And it was messy, it was icky, why would you study menstrual blood? And they persisted and they have, you know, are well on their way to developing what's hoped will be a diagnostic test. Why is that important? Because right now, the only way you can get an ironclad diagnosis of endometriosis is by having surgery and having it visualized. And that really needs to change.

• 13:03Regina Barber?

  Yeah, that would be amazing. So after reporting on this topic and like, taking stock of what's been going on for 10, 15 years of research, what is your outlook for the future of this field?

• 13:17Speaker 03

  I wish I could say that was like... Fantastically exciting, and it is by virtue of the researchers doing great things with not nearly enough money. I want to note for the nth time that the National Institutes of Health, the world's largest funder of medical research, spent something like 0.03% of its budget on this disease in 2024, which affects probably around 1 in 10 women of reproductive age.

• 13:55Regina Barber?

  Meredith, thank you so much for talking with us today. I learned a lot.

• 14:01Speaker 03

  I'm glad you did. I really enjoyed speaking with you, Gina.

• 14:08Regina Barber?

  For her part, Katie is hopeful about her future research while worrying about the future of research funding.

• 14:14Speaker 02

  We have some really exciting discoveries that I want to take forward, but the uncertainty with NIH is palpable. I have never felt such stress from everybody around me. If I don't get grants approved, then the lab shuts down. For the sake of endometriosis, for the sake of the young girls that are trying to avoid living the life that I did, that's what drives me.

• 14:48Regina Barber?

  This episode was produced by Burleigh McCoy, edited by Amina Khan, and fact-checked by Tyler Jones. The audio engineer was Robert Rodriguez. I'm Regina Barber. Thank you for listening to Shorewave from NPR.

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