How endometriosis research could shine a light on other diseases

• Endometriosis is an often debilitating condition that affects around 1 in 10 women, yet treatment options and funding remain limited
• Pioneering research approaches, such as using “organs on a chip,” could play a crucial role in deepening our understanding of the science behind endometriosis
• Improving our knowledge in this area could provide key insights that would help to treat immunological conditions that affect both men and women

Nearly ten years ago, Jo Cox, a British Member of Parliament told UK lawmakers “we are far more united and have far more in common with each other than things that divide us”.¹ In 2019, three psychologists published a paper that showed people are, in fact, more united than they are divided.²

And it would seem that this unity holds true when it comes to exploring the science behind women’s health as demonstrated by one condition in particular – endometriosis, a chronic inflammatory disease characterized by the growth of endometrium-like cells outside the uterus.

Endometriosis is a poorly understood condition that affects an estimated 200 million people who are assigned female at birth around the world.³ Despite its prevalence and the severity of this painful disease, funding remains limited,⁴ and a significant number of patients are left undiagnosed for years, and often without effective treatment options.^5,6

“There’s been a lack of awareness when it comes to endometriosis and it has been neglected for some time,” Andrew Horne, Professor of Gynaecology and Reproductive Sciences at the University of Edinburgh, says.

“But we are starting to see that endometriosis has many similarities with other conditions and it’s something that researchers are starting to tap into more and more as they try to better understand and treat the conditions they have been focusing on. Irritable Bowel Syndrome is one example of this. Like endometriosis, this is a chronic pain condition. There is a lot of crossover of symptoms,” Andrew says.

Despite the many outstanding questions that remain around endometriosis, Andrew says he’s looking to the future with optimism as more research consortia around pain and other chronic conditions unite with the community of scientists working on endometriosis.

On the other side of the Atlantic, Linda Griffith, professor of biological and mechanical engineering at M.I.T. and director of the M.I.T. Center for Gynepathology Research, and her team are combining engineering and biology to find the answers women and their healthcare providers are looking for when it comes to endometriosis.

Linda’s team is looking at how cells and molecules interact in the endometrium and why these interactions can cause inflammation. Their research reveals that understanding the science behind endometriosis could not only help the women battling this invasive disease but could also be intrinsically linked to other immune-mediated pathologies. Learnings that could teach us how to tackle a range of immunological disorders that affect both men and women.

By working out the ways in which cells make decisions, Linda and her team hope that it will be possible to find the medicines that can interrupt the causes of inflammation in endometriosis and modify the natural history of the disease. These insights could be translated into important lessons for a number of other immunological conditions, including Crohn’s Disease and arthritis.⁸

“When it comes to endometriosis, the immune system is potentially a huge protagonist, but we still don’t fully understand the mechanisms. It could be that there are deficiencies in being able to clear damaged tissue in the pelvic cavity and the body is simply overwhelmed. Or it could be that different patients have different weaknesses in their immune system,” Linda says.

“We’re trying to understand whether women may have systemic problems with their immune systems that are caused by prior or existing infection. There may be chronic conditions, such as Lyme disease, that are causing immunological changes and this could result in problems clearing the inflamed tissue,” Linda says.

Understanding the role of sex hormones when it comes to the immune system is also important, Linda says, noting men have stronger acute responses to most infections than women do, but women suffer disproportionately from auto-immune diseases and chronic effects of infections. Evidence is showing that women are more likely to have long COVID.⁹

“We know there are sex-based differences in immunology. Take Crohn’s for example. There is a greater prevalence in boys pre-puberty and in girls post-puberty,” Linda says.

“We also know that the endometrium grows very profoundly every month and there is a very coordinated role of immune cells. It may be that the micro-vessels in the endometrium are growing so well because they are receiving estrogen. There are still so many things that we don’t understand but that could give us important clues for regenerative medicine more broadly,” Linda says.

A key reason for the lack of progress and research in areas like endometriosis is the fact that people have been unwilling to talk about periods, Linda says.

“There’s still so much we don’t understand about the basic processes of menstruation and the squeamishness to even discuss menstruation tends to infiltrate all discussions of women’s health. We really need a moonshot for menstruation science. We need to adopt a scientific language that is divorced from social associations. Doing so will mean that we will be able to focus on the scientific problem and this will make it easier to gain buy-in from a wider group of people,” Linda says.

Linda points to the progress that has been made in breast cancer as one example of what can be achieved when the focus is firmly on the science behind the disease.

According to the World Health Organisation, age-standardized breast cancer mortality in high-income countries dropped by 40% between the 1980s and 2020.¹⁰ In the United States, the five-year relative survival rate for women with non-metastatic invasive breast cancer is 91%, and the 10-year relative survival rate for women with non-metastatic invasive breast cancer is 85%, data published by American Society Clinical Oncology (ASCO) show.¹¹

“Breast cancer was also once a taboo. This resulted in women being diagnosed late and then having to undergo radical mastectomies. Things started to change when women were elected to congress and they started to make it an issue. They were able to push through increased funding and chip away at the taboo nature. All of a sudden, research and clinical care started to become more attractive to the best clinicians and scientists,” Linda says.

Improved collaboration will play a crucial role in being able to advance research as well as the diagnostic and treatment options for the millions of people battling conditions, like endometriosis, every day, Linda says.

“We need a plan. We need teams. Just as the oncology community has successfully come together, we need to come together too,” Linda says.

Scientists have struggled to secure funding for endometriosis research for decades. In 2022, funding from the National Institutes of Health (NIH) for endometriosis accounted for a minuscule 0.038% of the total health budget. This equates to $2.00 per patient per year.⁴  By contrast, the total economic burden for endometriosis is estimated to be as high as $78-$119 billion each year in the US.¹²

“We should be breaking down the silos. We have to do things for ourselves. We can’t wait for the NIH. We need to think about how we can be creative so that we can get stuff done,” Linda says.

In 2012, Linda and her team at M.I.T. secured over $30 million in funding from the Defense Advanced Research Projects Agency (DARPA) and the NIH to develop a technology platform that would replicate human physiological systems in the laboratory.¹³

Linda and her colleagues were tasked with using engineered human tissue constructs to learn how 10 different organs would interact with each other for a month. These constructs, sometimes called “organs on chips” in lay language, are referred to as microphysiological systems (MPS) by funding agencies and scientists in the field.

“The aim was to see if we could use this technology to predict how effective and also how toxic drugs might be. For me this was an opportunity to use tissue engineering to build the technology that would allow me to study endometriosis,” Linda says.

Instead of trying to use petri dishes or animal models to explore systems biology, Linda and her colleagues at M.I.T. have developed ways to make MPSs with microvascular networks permeating the tissue, using microfluidics and special hydrogels that they have invented.⁷

These approaches are being used in research labs to model endometriosis lesions with patient-derived cells, to examine phenomena like vessel permeability and immune cell trafficking, and to test how drugs affect lesions, Linda says.

“The funding from DARPA and NIH enabled the development of powerful new tools for building 3D models of the endometrium and other mucosal barriers, like the gut. Some of these tools are now being commercialized and used around the world. It just shows how building new technology for a woman’s disease can be used more broadly,” Linda says.

Metrodora Institute is another example of an organization that is taking a creative approach to diagnosing and treating chronic disease conditions, Linda says. The US-based institute is modeling a more integrated way of approaching neuroimmune axis disorders – conditions that can be triggered by an infection, surgery, injury, or hormone change – by bringing together clinicians from different disciplines in one space.¹⁴

It is the first integrated multidisciplinary clinic in the US for people with these conditions. They have also established an innovation hub to collaborate with industry and academic partners.¹⁵

“As a scientist, I am thrilled to see the kind of clinical approach being taken at Metrodora, especially since they are building a superb research facility for building biobanks from their patients, including microbiomes and other precious samples. This kind of integrated clinical research center can speed the discovery of common mechanisms across many conditions that have similar symptoms of pain and fatigue, but may affect different organ systems,” Linda says.

A major challenge associated with endometriosis is the ability to diagnose it. It takes women 10 years on average to receive a diagnosis,⁵ but Martin Hund, Clinical Development Lead for Roche Diagnostics, is starting to sense a change in the diagnostics space.

“In the last five years, there has been a definite shift. There is a growing awareness of endometriosis, and in countries like Australia, France, and the UK, this awareness is going all the way up to a political level. We are seeing a slight increase in funding, but more importantly, we are seeing more start-up companies in the diagnostics field,” Martin says.

A key area of focus for start-ups is the development of non-invasive alternatives, such as blood tests, to the laparoscopies – surgical procedures – that women currently have to undergo in order to get a diagnosis. Scientists are also exploring whether analyzing differences in the cellular biology and genetics of women’s menstrual effluent, or menstrual blood, could provide a less invasive way of finding out why endometriosis only develops in certain women.¹⁶

Meanwhile efforts, including the Women’s Health Study: from Adolescence to Adulthood, led by Boston Children’s Hospital and Brigham and Women’s Hospital, are underway to collect samples, such as urine, saliva, blood, cells, tissue, and peritoneal fluid, from females from adolescence to adulthood in order to gain deeper insights into the early stages of women’s health issues that can occur over their lifespan.¹⁷

It is becoming increasingly clear that shining a light on conditions like endometriosis will also make visible many of the solutions that researchers, clinicians, and patients may be searching for in other disease areas, underscoring the magnified return on investment when it comes to investing in women’s health.