Driven by the pain of endometriosis, this scientist is uncovering clues to its causes

When she was a teenager and the pain became agonizing, Katherine “Katie” Burns would crawl under her bed and lie bellydown on the wood floor. She’d clutch a calculator and do “random” math problems to distract herself from the feeling that invisible hands were wringing out her uterus like a washcloth. In Burns’s childhood home in rural Pennsylvania, menstruation, sex, and reproduction weren’t welcome topics of conversation, but her parents shuttled her from doctor to doctor searching for the source of her pain—which had visited her occasionally since she was 10 or 11 and became a constant presence once she got her period on the eve of her 13th birthday. “They said it was growing pains. It was normal. It was nothing,” recalls Burns, 47, a pathobiologist and toxicologist at the University of Cincinnati (UC). “They took me out of the room and said to my parents: ‘This is psychological. She’s seeking help.’” It wasn’t until Burns went away to Gettysburg College that she learned from her roommates that the pain that kept her in her room on Friday nights and that several times sent her to the emergency room wasn’t normal. Nor were the periods that soaked a super-plus tampon every hour, or her need to take ibuprofen constantly to be able to function. She went to a gynecologist, who asked whether she had perhaps forgotten to extract a tampon. Eventually, a different gynecologist conducted a thorough physical exam and located a mass sitting under the skin on the right side of her pubic area. In March 1999, weeks before her 21st birthday, Burns underwent surgery and the mass was extracted. It relieved some of the pain. It also offered validation. Microscopic examination of the mass showed Burns had endometriosis. “It was a relief,” she recalls. “There was actually something that was wrong. I wasn’t making this up.” In endometriosis, tissue resembling the endometrium, the lining of the uterus, which is shed each month during menstruation, grows outside of it, mainly in the pelvis. The misplaced tissue can lead to intense pain during periods; chronic pelvic pain; pain with sex, defecation, or urination; and infertility: An estimated 33% of women with the disease are infertile. But although endometriosis probably affects about one in 10 reproductive-age women—an estimated 190 million worldwide—its origins remain murky and the only treatments target the pain, not the origins of the disease. One reason is that research on endometriosis has been chronically underfunded. Between 2010 and ’24, the National Institutes of Health (NIH), the world’s largest medical research funder, spent an average of $14.5 million annually—0.039% of its average budget over those years—studying the disease (see graphic, below). Research on endometriosis “is so far behind because it affects women. And it doesn’t kill you,” Burns says. Her own search for relief would morph unexpectedly into a life spent in the lab tracking the roots of the disease as part of a cadre of determined scientists, several of them with endometriosis themselves. Researchers have long pursued the role of hormones: Estrogen turbocharges growth of the maverick tissue, which often resists the calming, antigrowth effects of progesterone. But Burns and others have set their sights on the immune system, revealing that it not only fails to clear the errant growths, but seems to be essential to their establishment and flourishing, as lesions become epicenters of chronic, low-grade inflammation that can affect the whole body. Their work has suggested new, immune-related targets for endometriosis drugs as well as the possibility of diagnostic tests for a disease that still takes, on average, 7 years to identify. Burns herself is pursuing such a test, but in an increasingly tight NIH funding environment, there are no guarantees she will be able to keep the work alive. The explosion of findings on immune dysfunction is a welcome development, says Stacey Missmer, an epidemiologist at the University of Michigan and president of the World Endometriosis Society, who herself has the condition. “We for so long have been focused on estrogen and progesterone,” she says. “We’re at this wonderful point of discovery where we are embracing nonhormonal underpinnings that are really holding up in evidence.” At the age of 8 or 9, Burns had informed her mother—who herself had a master’s degree in biophysics and supervised her daughter’s science experiments growing fungus on petri dishes—that when she grew up, she planned to work with microscopes at NIH. In 2000, 18 months after her diagnosis, she began a Ph.D. program in pathobiology at Pennsylvania State University, with a concentration in toxicology that would lead her into research on liver metabolism. The lab was male dominated, Burns recalls, and the pain that often incapacitated her “was not really an accepted topic.” That pain arises from inflammation and scarring in and around endometriosis lesions, and from nerves that infiltrate them. Most lesions are superficial, growing on the peritoneal membrane, which lines the walls of the pelvis, envelops the ovaries and the fallopian tubes, and drapes parts of the ureters, bladder, and bowel. The ovaries are a common site, and here lesions can develop into large cysts called endometriomas (see graphic, below). The aberrant tissue can also reach deep into the muscular walls of the bowel, bladder, and vagina. And it commonly affects certain ligaments that hold the uterus in place. In rare cases, it colonizes the diaphragm, liver, chest cavity, or lungs, which can cause people to cough up blood or become breathless when a lung collapses. Like many with endometriosis, Burns was disappointed by the few treatment options. Standard birth control pills combining a synthetic version of estrogen with the progesterone analog progestin are a first-line treatment that reduces natural estrogen production to ease pain. But they caused her intolerable, splitting headaches and bloated, painful breasts. (Beyond the potential side effects, such therapy is also a nonstarter for those trying to get pregnant.) Other hormone-based therapies come with their own hazards including hot flashes, night sweats, and, with prolonged use, bone thinning. Nor was surgery a panacea. Still required for an ironclad diagnosis of endometriosis, it can also ease symptoms by removing lesions, although they can be exceedingly tricky to spot and less practiced surgeons routinely miss them. Even after clean removals, the disease often recurs. Burns had three surgeries by early 2004, each of which found her pelvis increasingly riddled by endometriosis deposits and adhesions—bands of scar tissue that misshape and tether organs to each other or to the walls of the pelvis. The pain would recur months after each procedure. She would wake at night moaning, nap from exhaustion, then log extra hours in the lab evenings and weekends to try to keep up. She carried petri dishes with two hands because the pain made her hands shake. That year, in desperation, she enrolled in an NIH-run study to treat endometriosis pain with a drug called raloxifene that, it was hoped, would block estrogen-stimulated lesion growth. Fortunately for Burns, she received a placebo, because the drug worsened pain in those who received it. But the trial changed Burns’s life by introducing her to the NIH physician-scientist running it, OB-GYN Pamela Stratton. She understood endometriosis like no other medical professional Burns had met, and her team was doing science in pursuit of a cure. “Just seeing that somebody cared about the disease, that they were trying to understand it, was pivotal in my saying, ‘I am done with liver research and I want to try this,’” Burns recalls. Late in her Ph.D., Burns began to look for a postdoctoral position that would let her study endometriosis. Next to no one was doing such research. But in 2007, Kenneth Korach, a reproductive endocrinologist and leading authority on estrogen receptors at NIH’s National Institute of Environmental Health Sciences, found her a place in his lab. When Burns entered the field, not much more was known about the cause of endometriosis than when American gynecologist John Albertson Sampson in 1927 proposed what became the widely accepted, and still-dominant theory, known as retrograde menstruation: Menstrual blood seeds lesions by flowing backward through the open-ended fallopian tubes and out into the pelvic cavity. In recent decades, some researchers have questioned whether that theory can explain a disease now understood to have multiple forms—deep, superficial, and endometriomas—with different biology and, plausibly, distinct origins. One alternative theory suggests stem cells that are endometrial progenitors seed the pelvic cavity, in some cases long before puberty. Their possible sources include the adult endometrium, the bone marrow, and retrograde flow during vaginal bleeding that occurs in 5% of female newborns. That would explain why some girls, like Burns, have symptoms before their first period. So would an even older theory than Sampson’s, that normal peritoneal tissue, which develops from the same early embryonic cells as the endometrium, transforms into endometriosis lesions. This would also account for patients with lesions far from the uterus, on the diaphragm and in the chest cavity. Because 90% of women with healthy, unoccluded fallopian tubes have some degree of retrograde menstruation and only a fraction develop the disease, researchers had also long suspected that failures or aberrations of the immune system allow the misplaced cells to survive. Immune cells are known to inundate the peritoneal cavity of people with endometriosis. But these were initially assumed to simply be reacting to the stray tissue. Evidence that the immune system might actively drive inflammation and disease progression, rather than simply failing to clear lesions, was only beginning to attract wider attention as Burns began her research. In Korach’s lab, Burns first set out to develop a mouse model of the disease. Only humans and other primates develop endometriosis naturally, but Burns mimicked the condition in rodents by mincing uterine tissue from one mouse and injecting it into the peritoneal cavity of another—which was genetically identical, to prevent rejection of the foreign tissue. The work, published in Endocrinology in 2012, revealed that lesions were fewer, smaller, and less likely to grow in size if either the donor or recipient mice were engineered to lack a key estrogen receptor on their cells, reaffirming the role of this hormone in lesion growth. But what jumped out at Burns was another finding: Even in recipients that not only lacked the key receptors, but also had their ovaries removed and thus produced almost no estrogen, rudimentary endometriosis lesions developed. These didn’t grow and flourish, but something was allowing them to take root. Burns decided to explore what was happening during the first hours and days after injecting the tissue in the mice. “She was productive. She was creative. She worked extremely hard,” Korach recalls. She never mentioned her disease in his presence, he adds. “She was tough. She shouldered it.” - Katie Burns - University of Cincinnati But Burns’s pain was in fact so bad that she was again considering surgery. By 2009, scarring and inflammation from the disease and five previous operations had left her ureters “like concrete,” her surgeon told her. Trying to free them and her other pelvic organs risked more damage that could leave her catheterized for life. “How am I going to live like this?” she remembers asking herself. “Am I going to live with this?” Luckily, Burns found a physician who helped her persist with a nonsurgical treatment that she found she could tolerate, after getting over the uterine spasms it initially induced: an intrauterine device that releases progestin, which dampens inflammation, suppresses production of disease-driving estrogen, and, in some cases, can inhibit lesion growth. More important, Burns says, she got connected with a pelvic floor therapist whose weekly work began to release muscle tightness and “unstick” her insides. For the first time since she was 10 or 11 years old, Burns rated her pain a two or three on a scale of 10, instead of the six or seven where it had hovered for years. And for the first time in just as long, she began to socialize, because she wasn’t afraid that pain would force a last-minute cancellation of plans. She went to see Wicked. She walked with friends. She could now bend over without paralyzing pain, so she planted zucchini and basil and tomatoes and vinca in the garden of her townhouse. And she began to do science without feeling so hamstrung by the disease. As Burns engaged in her studies with new vigor, the field of endometriosis research was becoming more energized, too. In 2014, the same year that advocates launched an annual, worldwide march for endometriosis funding, scientists published the first molecular classification system for the disease and a much-needed set of standards for biobanking endometriosis samples; today, 66 centers in 24 countries have banked more than 10,000 samples. Some scientists began to tease out the roles of multiple genes in the condition. About 50% of disease risk is thought to be inherited, though the genetic loci identified so far make only small contributions. (Environmental triggers including chemicals and diet may also play a causal role, though more research is needed.) Separately, several teams were beginning to illuminate just how dysfunctional the immune system was in people with endometriosis, using patients’ blood and peritoneal fluid, which bathes the pelvic and abdominal organs. Studies had already revealed that the numbers and potency of natural killer cells, an important class of innate immune cells that recognize and destroy errant cells, were reduced in patients. Now, new papers found that these natural killer cells had few activating receptors and many inhibitory ones, and were failing to release key cell-killing chemicals. Neutrophils, another set of immune cells that are typically the first to flock to foreign tissue, engulf it, and dispose of it, also seemed to be malfunctioning. Lab studies suggested something in patients’ peritoneal fluid induced neutrophils to pump out excessive amounts of the growth factor VEGF, which promotes blood vessel growth and could be helping the lesions establish their own blood supplies. And the neutrophils failed to die on schedule, instead secreting chemicals that in the body would draw even more of themselves to a lesion. Finally, a glut of findings was implicating a third class of innate immune cells, the macrophages that should flock to the scene soon after neutrophils to hoover up errant tissue. In the peritoneal fluid of women with endometriosis, macrophages were not only failing to take up menstrual debris, but they were actively secreting inflammatory molecules that promoted blood vessel growth and sent survival signals to the maverick cells. Advancing on Burns’s mouse model, reproductive biologist Erin Greaves, then at the University of Edinburgh, explored the role of macrophages by giving rodents estrogen and progesterone to prompt artificial menstruation. Greaves, now at the University of Warwick, inserted tissue shed from the “menses” of one mouse into another, tracking its resident macrophages and showing they contributed to lesion formation—the first causal evidence that immune cells from menses were playing a role in establishing lesions. Burns, meanwhile, was using her mice to explore the very earliest stages of disease. In the first 24 hours after the animals were injected with minced uterine tissue, before lesions were even established, an army of neutrophils and macrophages had flooded the scene, she found. Within 72 hours, lesions took hold and began developing a blood supply—all in mice lacking almost any estrogen and without key estrogen receptors. Only after 72 hours did the role of estrogen in supporting and maintaining the lesions commence. The work, published in Endocrinology in 2017, suggested that lesion development at first depends on immune cells, before estrogen begins driving it. This two-stage model answered a question born of Burns’s own experience: Why are estrogen-manipulating therapies sometimes ineffective? The results “showed that the immune system was of critical importance for the establishment of peritoneal lesions,” says James Segars, an OB-GYN and endometriosis researcher at the Johns Hopkins University School of Medicine. “That’s righteous. That’s really important.” (Segars, who describes himself as a “big fan” of Burns’s, was on her surgical team during an operation that was part of the NIH raloxifene study in 2004 and has lobbied with Burns for endometriosis funding on Capitol Hill.) By the time of that paper’s publication, Burns had landed a tenure-track job at UC. Although many labs studying the immune system in endometriosis were focused on macrophages, which are hardy and long-lived in the lab, making them easier to study, Burns decided to focus on neutrophils—“a cell type that people have really thrown out,” literally and figuratively, she says, partly because they are famously hard to keep alive. She also turned toward a new source of biological samples that would allow her to study humans and not just mice: the products of menstruation from people with and without the disease. Burns wasn’t the first to seek insights from menstrual effluent (ME)—so-called because it contains much more than simply blood, including endometrial tissue fragments, and is distinctly different in composition from peripheral blood. Scientists running a project called Research OutSmarts Endometriosis (ROSE) pioneered the study of ME, collected mostly in menstrual cups—small, over-the-counter, reusable silicone cups inserted in the vagina to capture the fluid. Their results have shown differences between samples from participants with and without the disease that point to potential noninvasive diagnostic tests. Their single-cell sequencing, for example, revealed that natural killer cells were dramatically depleted in the ME of people with endometriosis, reflecting the earlier findings from peritoneal fluid. When the study launched in 2013, “people literally laughed at us,” recalls Christine Metz, an immunologist at the Feinstein Institutes for Medical Research who co-leads the effort with geneticist Peter Gregersen. Menstrual blood was messy, it was imprecise, it was difficult to collect, OB-GYNs told the pair. Why bother when the disease could be diagnosed with surgery? But the Feinstein team has since enrolled more than 3000 participants and is now one of several pursuing ME tests based on differences in the proteins or RNA expression in the fluid. “There’s something to be discovered here, and we’ve already shown that in the data,” says the ROSE study’s clinical research coordinator, Amber Seecoomar. “If we could really create a screening or a diagnostic tool, we could change thousands of lives.” In 2020, Burns’s team began the painstaking work of studying neutrophils from ME samples. Compared with the neutrophils in peripheral blood, these cells are even more short-lived and fragile, prone to bursting during centrifuging or succumbing to dyes and buffering solutions. The results, published in JCI Insight in January, revealed abnormalities in ME collected from women with endometriosis on day one of menstruation, indicating the aberrations were there from the moment the retrograde flow entered the peritoneal cavity. Endometriosis samples had higher proportions of neutrophils that promote blood vessel growth, and of older neutrophils. Normally, neutrophils die within hours; those that persist encourage inflammation, a state thought to be conducive to lesion survival. The paper also described work in mice that bolstered the idea that neutrophil activity in endometriosis represents a healthy process run amok. Examining tissue samples, Burns showed that neutrophil extracellular traps—adhesive meshworks of packed DNA and proteins that the cells normally produce to entrap microbes—were offering the errant cells a foothold, allowing lesions to get established. Perhaps, Burns’s team suggested, aged neutrophils are attempting to “rescue” retrograde menstrual tissue, similar to a wound-healing response. The misguided rescue happens with each menstrual cycle, reinforcing the inflammatory environment that caused the previous month’s damage. The immune-related discoveries by Burns and many others haven’t led to any approved treatment. But several clinical trials targeting the immune system are edging along. A Chinese company called Hope Medicine last fall reported significant improvements in pain in patients treated during a phase 2 trial of HMI-115, an antibody that locally attacks the prolactin receptor in endometriosis lesions. Prolactin is a hormone that attracts and activates neutrophils, promotes blood vessel growth, and activates nerves in lesions, spurring pain. Another antibody, AMY109, made by Chugai Pharmaceutical, attacks interleukin-8, an inflammatory cytokine pumped out by macrophages and neutrophils drawn to the site of misplaced tissue. It shrank lesions and reduced scarring in monkey studies and was shown to be safe and well tolerated in an initial human trial. The company last year launched a larger, phase 2 trial. Findings by other researchers not yet in the clinic are pointing to the potential of checkpoint inhibitors, drugs made famous in cancer immunotherapies, in endometriosis—for instance to restore the cell-killing ability of natural killer cells. And a team at the University of Edinburgh is preparing to launch a pilot trial of a compound called nibrozetone that targets macrophages, improving their cell-eating ability and nudging them away from their wound-healing, lesion-supporting tendencies. All of the activity makes Missmer confident that “the next wave of successful treatments will be in the immunology and inflammation realm.” In her office, in Cincinnati, Burns keeps a teal heating pad draped over her desk chair. She lays it in her lap or slaps a lidocaine patch on her lower abdomen to manage her pain, which is less frequent these days. A not-so-obvious cost of her disease has been a sense of not fitting in, Burns says. Her isolation through her youth and young adulthood has made relationships difficult. She didn’t feel she could engage with a prospective partner knowing she was likely infertile. Carrying that knowledge was hard; there were times when she fled church during baptisms. Years of therapy have helped her both grieve and battle her introversion. And her experience has made her a rock for others with her disease, among them her sister, her pelvic floor therapist, and an endless stream of people who reach out to her by email. People with endometriosis “get desperate and will do almost anything to find answers,” she says. “I found it quite shocking that people would send me their medical records, but it happens quite a bit.” Burns’s first graduate student, Taylor Wilson, arrived in the lab having lived in silence for years with symptoms of endometriosis. (She has not had diagnostic surgery because, she says, her insurance declines to pay for it.) Wilson says Burns can “look at me and know exactly when I’m not feeling well, and she’ll be like, ‘OK, what’s going on?’” Wilson, whom Burns draped with a Ph.D. hood earlier this month, was the first author on the January neutrophil paper. In the course of their painstaking experiments, Wilson and Burns also discovered something else in the ME of women with endometriosis, something not yet published and so dramatic that UC’s tech transfer office filed patent applications on their behalf. Under a microscope, the neutrophils from the ME of women without endometriosis had plump, purple-stained nuclei, each with the usual two or three lobes. But in the ME of those with endometriosis, these nuclei had four, five, or even more lobes, yet they were condensed and shrunken. The cytoplasm of these cells was pockmarked with white spaces from storage sacs called vacuoles. “It shocked us. It’s absolutely beautiful,” Burns declared as she displayed a slide showing the neutrophils in ME from women with and without the disease at a June meeting* at the New York Academy of Sciences. Linda Griffith, a biological engineer at the Massachusetts Institute of Technology who is developing chip-based devices with endometrial lesion tissue to better study the condition in the lab, and who has the disease herself, says Burns asked a “really great question” about visual differences between cells, and “hit the jackpot” with the finding. The difference in neutrophils is so “blindingly obvious” that if it plays out in a larger number of people, it could “very quickly,” become a diagnostic test, adds another meeting attendee, Michael Rogers, a biologist who is developing endometriosis therapies at Boston Children’s Hospital. Such a test could be less complicated and thus possibly cheaper than other ME tests being developed using measures of RNA expression and proteins. Burns and Wilson now have data supporting the test from more than 30 volunteers; to win funding, potential investors have suggested they’ll need closer to 200. But Burns first has a bigger hill to climb. Her lab, which was flush with cash as recently as 2024, is in danger of closing for lack of funding. Her single NIH grant ran out last year, and bridge funding from her university ran out in June. She has numerous NIH grant applications out. “The funding situation right now is very—it’s very difficult,” Burns says. “It’s not just my lab. It’s everybody studying endometriosis.” At the NIH institutes that have supported Burns’s work in the past, fewer than one in 10 grant applications are being funded. The long odds may reflect uncertainty in the face of a 40% NIH funding cut President Donald Trump’s administration has requested for 2026, as well as a new NIH policy requiring some multiyear grants to be fully funded immediately. Burns is now pouring all her energy into keeping her lab alive. “We really need to recognize how debilitating endometriosis is. How underfunded endometriosis is. And how hard investigators have to fight to be able to study this disease.” Data Both chartsThe total U.S. population living with each condition and prevalence data reflected in each chart were derived from the following sources: - The Centers for Disease Control and Prevention (CDC) does not publicly report endometriosis data or estimates of prevalence in the U.S. population. Instead, estimated prevalence was drawn from Shah et al. (2013) and applied to U.S. Census Bureau population estimates for 2024 to calculate the percentage of women in the United States affected by endometriosis. The Shah et al. paper assesses endometriosis prevalence in the Nurses’ Health Study II. The authors report participants’ baseline prevalence upon study entry at 6.5%. During the following 22 years of the study, an additional 5504 study participants were diagnosed with endometriosis, or 4.7% of study participants. We combined the two percentages to arrive at a lifetime prevalence of 11.2%. - The estimate of the number of people in the U.S. with diagnosed diabetes is from CDC’s National Diabetes Statistics Report, published in 2024. The total is a crude estimate from 2021. - The estimate of the number of people in the U.S. with current asthma is from CDC’s Most Recent Asthma Data, published in 2024. The total is a weighted estimate from 2022. - Breast and prostate cancer: The number of people living with breast cancer and prostate cancer is published in the American Cancer Society’s Cancer Treatment and Survivorship Statistics, 2025 report. - Prevalence data for diabetes, asthma, breast cancer, and prostate cancer are from CDC’s 2024 National Health Interview Survey. Estimates from available surveys and databases were compared to assess accuracy. Final source decisions were informed by CDC’s press office and disease experts. One in 10?Prevalence reflects the estimated number of people with a disease out of the population considered to be at risk for that disease. The following definitions of at-risk populations underlie the estimates of adult disease prevalence: - Endometriosis: lifetime of girls and women - Prostate cancer: men 50 years and older - Breast cancer: women 18 years and older - Diabetes and asthma: adults 18 and older See above sources for more details on prevalence methodology. Deeply discountedPer capita research spending for each condition was calculated by dividing the National Institutes of Health’s 2024 funding for each disease, as reported in the categorical spending report, by the estimated number of people living with each condition in the U.S. The number of people with endometriosis was calculated by applying the Shah et al. (2013) estimated prevalence rate to the 2024 U.S. Census population estimates of the total population of women 15 to 49 years old, which corresponds with female reproductive age. Per capita spending for breast and prostate cancer was derived using the number of people living in the U.S. with breast and prostate cancer as of 1 January. Data on the number of people living with breast cancer and prostate cancer are from the American Cancer Society’s Cancer Treatment and Survivorship Statistics, 2025 report and reflect all breast and prostate cancer cases collected by the North American Association of Central Cancer Registries. Physicians in all 50 states are required by law to report newly diagnosed cancers.