Endometrial Organoids Open a Window into the Womb

When she was in junior high school, Linda Griffith started experiencing stabbing pelvic pain that would have her curled up in the fetal position for hours. Years later, a doctor would finally pinpoint the cause: Like nearly 10 percent of menstruators, Griffith suffered from endometriosis, where cells resembling those from the uterine lining grow outside the uterus.

But until she received this diagnosis, doctors largely dismissed her pain. Unable to understand why she was suffering, Griffith found solace in something she could understand: math. “I loved math because math was a place where everything made sense,” recalled Griffith, who is now a bioengineer at the Massachusetts Institute of Technology (MIT). “My body wasn’t making sense…and so math was a really good way to have a little anchor in my life, of sanity.”

Almost equally fond of chemistry and biology, Griffith pursued chemical engineering for her graduate and undergraduate studies before pivoting to bioengineering. Through her scientific journey, she has pioneered approaches in tissue engineering, including growing a human ear-shaped cartilage structure on the back of a mouse and commercializing a process to build 3D-printed, FDA-approved biomaterials.¹

Griffith also championed the need to steer away from using animals to model human diseases. To this end, after decades of engineering liver and bones in culture, she shifted her focus towards developing endometrial organoids—tiny, endometrium-like structures that mimic the tissue in a lab dish. These offer an in vitro platform to study and screen drugs for diseases such as adenomyosis and endometriosis.

From Georgian Swamps to Tissue Engineering

Griffith’s upbringing planted the seeds of scientific temper and an inquisitive mind. Growing up in South Georgia near the Okefenokee Swamp, she had an outdoorsy childhood where she played with fish, frogs, and snakes. “There was a lot of interaction with nature,” recalled Griffith.

Summers in Georgia came with rain and thunderstorms. Her father used this opportunity to teach her to tell how far away lightning was by calculating the time between thunder and lightning. “So, the idea that you could understand the world around you through physics and chemistry and math was something I grew up with,” said Griffith. “That was a natural thing.”

As her body began to limit her when she hit puberty, she sought control in the world of science. With the oil crisis looming nearby, the world needed chemical engineers, driving her to explore this field for her undergraduate and graduate studies. “At the time, there was no bioengineering,” said Griffith. She eventually received her PhD from the University of California, Berkeley in 1988.

So, the idea that you could understand the world around you through physics and chemistry and math was something I grew up with.

—Linda Griffith, Massachusetts Institute of Technology

Around that time, as scientists increasingly understood the molecular aspects of biology, Griffith became interested in connecting engineering to the life sciences. She found herself focused on healthcare applications and regenerative medicine in Robert Langer’s lab at MIT for her postdoctoral research, before joining the institute faculty in 1991.

Through the 1990s and 2000s, she worked on designing better biomaterials and scaffolds that would regulate cell behavior, which was crucial for engineering tissues in the lab.^2-4 She helped design systems that would allow cells to organize themselves in three dimensions and interact with neighboring tissues to ensure that the in vitro system mimicked the organ’s in vivo physiology.^5-7 In this way, she developed in vitro platforms to study the liver and bone, which contributed towards a better understanding of liver regeneration and cartilage and fracture repair.^8-10

Even though she engineered bones and livers in the lab, she never thought about leveraging her expertise to study the organ that troubled her for most of her life: the uterus. A combination of several events in the mid-2000s changed that.

Shifting Gears to Study the Endometrium

After receiving her endometriosis diagnosis in 1988, Griffith underwent several operations. Through these, she met Keith Isaacson, a gynecologist and surgeon at Newton-Wellesley Hospital, who provided the initial push to pursue endometriosis-related research. “[Isaacson] was very, very frustrated with how slow progress was in new therapies,” recalled Griffith. “And so, he was begging me [to work in the field].”

Around the same time, she saw her niece struggle with medical gaslighting and suffer for years before getting an endometriosis diagnosis, which added fuel to the fire. “Her situation was a lot like mine when I was in high school, and so it was very, very frustrating,” said Griffith. “I was really upset that all these years later there’s no taking young women seriously when they present with the disease.”

The turning point came in 2007 when Susan Whitehead, one of MIT’s trustees, invited Griffith to speak about how her work could benefit women at a luncheon for women in science and engineering. As somebody who engineered bones and livers, but did not work towards women’s health specifically, Griffith was stumped. “It made me think in the back of my head that maybe I should be thinking about this more,” she said.

All of these factors culminated in her pivoting her research focus towards endometriosis. In 2009, she founded the MIT Center for Gynepathology Research. Today, she codirects the lab with Isaacson.

Looking back, Griffith admitted, “For me to pivot to gynecology was a big career risk in certain ways.” However, coming from a bioengineering background and armed with her own experiences of battling endometriosis, she was confident that she would figure things out. “But anytime you go into a new disease area, there’s a steep learning curve.”

For her, this curve involved applying engineering principles to studying endometriosis, a complex disease whose molecular and cellular basis is poorly understood. To bridge this gap, Griffith and her team mapped the molecular profiles in the peritoneal fluid of several endometriosis patients and identified signatures of inflammatory networks linked with varied symptom severity.¹¹ In addition to providing a potential diagnostic signature, this data offered important clues that would come in handy while modeling the disease in vitro. Such a platform would pave the way to both better understanding the disease biology and screening drugs, which was challenging using in vivo platforms. As somebody who wanted to move away from modeling human diseases in mice, Griffith often advocated the need to engineer tissues in vitro using organoids or microphysiological systems like organ-on-a-chip models in conferences and consortia.

It was at one such consortium around mid-2010s, where Griffith met Ji-Yong Julie Kim, who researches uterine pathologies such as endometriosis, fibroids, and endometrial cancer at Northwestern University. “She was a force to be reckoned with,” recalled Kim, whose team was building a microphysiological system of the female reproductive tract. “I was very encouraged to see an engineer, a bioengineer, interested in women’s health, and especially endometriosis.”

An Engineering Approach to Women’s Health

Around the late 2010s, scientists started developing organoids from epithelial cells obtained from human endometrium, transforming the experimental landscape to study the tissue.^12,13 To get a more complete picture of the human endometrium in a dish, Griffith sought to coculture uterine epithelial cells along with stromal cells that support them. But she ran into a challenge.

Scientists traditionally use a jelly-like substance to mimic the extracellular environment in vitro. However, the components of this material can hinder the crosstalk between epithelial and stromal cells. Griffith and her team created a synthetic hydrogel to substitute the conventional gel, helping them culture endometrial organoids.^14,15

As her endometriosis-related research accelerated, it became increasingly difficult to juggle research in the areas of liver, bone, and endometrium. So, she hit the brakes on her work related to bone regeneration. “But liver is actually very important for endometriosis, because endometriosis is a systemic disease, and the liver plays an enormous role in regulating sex hormones and…[it] gates tolerance and immunity,” said Griffith. Her lab now focuses on both modeling the liver and endometriosis.

Juan Gnecco joined the team in 2018 as a postdoctoral researcher, having collaborated with Griffith during his graduate studies to build a uterus-on-a-chip. “We were biologists trying to do engineering; they [were] engineers trying to do biology,” said Gnecco, who is now a reproductive engineer at Tufts University.

As a postdoctoral researcher in Griffith’s lab, Gnecco leveraged the lab-made synthetic hydrogel to culture endometrial epithelial organoids along with stromal cells. Using this, the team built a system that captured crucial cell-matrix communication and mimicked key processes across the menstrual cycle in response to appropriate hormones, providing a platform to better study the human endometrium.¹⁶

Griffith and her team have also been working to create such model systems from the cells of people with endometriosis. These could offer insights about the disease and help test drugs.

“Linda was, for the most part, very supportive in all of the endeavors that we would go through,” recalled Gnecco. Griffith gave all her lab members the freedom to explore their own projects, “and that to me is the fun part of science,” he added. He said that he now tries to embody a similar approach while running his lab.

Griffith’s work has inspired others in the field by highlighting the possibilities in vitro systems can offer. “[Griffith] let us know about the different kinds of engineering systems that are out there,” said Kim, whose team used a microfluidic system similar to that used by Griffith.¹⁷ “It’s really been an eye-opening experience to see these kinds of advancements so that we can understand biology better.”

Advocating for Women’s Health-Related Research

Beyond the bench, Griffith has been vocal about her struggles with endometriosis—for which she underwent multiple surgeries—and breast cancer. She emphasizes the need to do better in women’s health research, which attracted like-minded people to her lab. “I have a lot of students who want to do advocacy for women’s health,” said Griffith.

“The part that I appreciate the most out of Linda as a scientist is her own experience and advocacy for women’s health or specifically endometriosis,” said Gnecco. An important lesson she imparts through this, according to him, is “not just doing science for science, but really trying to have that impact on patients.”

Kim believes that the world needs more people who are vocal about the need to do better research on women’s health. “It’s embarrassing what’s out there for women, for these treatments. So, the only way we can make steps is by being very loud about it,” said Kim. “[Griffith] really is a trailblazer.”

For Griffith, the approach to advocacy and inspiring the next generation is simple. “You go work on [solving the problem] and show them that there’s a way to do it, and get them excited about that,” said Griffith. “I think I’ve been able to get a lot of people excited about how to think about complex diseases like endometriosis.”