Like many people with endometriosis, Linda Griffith, a bioengineer at the Massachusetts Institute of Technology (MIT), struggled with terrible periods for years before receiving a diagnosis. For too long, doctors told her that the unbearable pain, heavy bleeding, fainting, and vomiting she experienced each month were normal. Even though endometriosis affects as many as one in ten reproductive-aged women, relatively little is known about the mechanisms that drive the disease (1). For many, the available treatments do not sufficiently treat the disease-associated pain, bleeding, and infertility.
Griffith’s early tissue engineering research largely focused on liver and bone tissue, but in the late 2000s, she began to feel compelled to address the startling lack of research on endometriosis. In 2009, she founded the MIT Center for Gynepathology Research. Today, she builds endometrial organoids from patients’ own cells to explore the pathogenesis of the disease and test new treatments.
How did you begin working in tissue engineering?
Starting in 1988, I did a postdoctoral fellowship in regenerative medicine with both Bob Langer, a chemical engineer at MIT, and Jay Vacanti, a liver transplant surgeon and tissue engineering researcher at Harvard Medical School. Afterwards, I took a faculty job at MIT. At the time, there was a huge need for engineers to get more involved in biology. A lot of engineers work on medical things like imaging or devices, but to do tissue engineering well, researchers actually have to know a lot of molecular cell biology. The molecular cell biology field was in its early stages then, and there weren't many engineers who knew much cell biology. When I started as a faculty member at MIT, I focused on designing biomaterials that would control the behavior of cells through their receptors.
Then in the mid 1990s, I had an epiphany about tissue engineering. Many diseases are not well understood, so it seemed obvious to me that tissue engineering could be used to build models of humans to study drugs and disease properties. In 1998, we started a whole new department called biological engineering to focus on tissue engineering for disease research and other open questions.
What prompted you to study endometriosis?
I've had nine surgeries for endometriosis. So, there’s a family element: my niece has it; I have it. There are many problems in gynecology that are understudied. That’s partly because the NIH has not traditionally offered a lot of funding for gynecology. So women who experience debilitating pain and bleeding may be told, “well, that’s normal.” What I went through was certainly not normal. And students today, decades after I went to school, are still suffering and missing exams. They’re not getting diagnosed, not getting treated, and they're thinking that something is mentally wrong with them. I decided that if I really wanted to do something for women, the most important thing would be to solve one of their biggest problems, to help the women who can’t get out of bed because they’re bleeding. It's not popular, but it's really important.
What are some of the limitations of current testing and treatments for endometriosis?
Over the past decade, almost all of the new drugs for endometriosis have been some version of a gonadotropin-releasing hormone (GnRH) agonist or antagonist. I’ve taken a lot of different versions of these, and the side effects were far more horrible and the therapeutic effects far less positive than advertised. Why don't we have any classes of drugs that aren’t hormone modulators?
When I was diagnosed with breast cancer, I got biomarker testing to find out that the cancer was triple negative, which made me wonder why we couldn’t do similar testing for endometriosis. My husband, Doug Lauffenburger, who is also a bioengineer at MIT, Keith Isaacson, a gynecologist at Mass General Brigham, and I have been on a mission to do that.
What other types of drugs have you investigated?
We characterized some patient samples to determine if there are subsets of endometriosis and identified a potential new nonhormonal target: c-Jun N-terminal kinase, or JNK. Stephen Palmer, who was at Merck at the time, had championed JNK inhibitors for treating endometriosis. He was part of the team that showed that these inhibitors were effective in two different animal models of endometriosis: rodents and baboons. Merck commissioned a clinical study, but didn't get results that would let them move forward with this particular drug.
Why did you want to build tissue models of the endometrium?
After this trial, we realized that we needed better models to test potential endometriosis drugs — not just animal models, but models that represent real patients. I got a Defense Advanced Research Projects Agency (DARPA) grant to build a “body-on-a-chip” with ten interacting organs.
We developed a powerful and useful way to grow organoids in a synthetic hydrogel. The nice thing about the synthetic gel is that we can put immune cells and stromal cells and blood vessels in it.
Steve and I have extremely strong faith in the potential of JNK inhibitors, so we independently got grants from the National Institute of Child Health and Human Development to support our work exploring them. We’re putting immune cells in our microfluidic devices so we can have real models of lesions with real hormone variations. Now we have companies approaching us to use our models to test various drug targets.
It’s a really exciting time for endometriosis research, and I am committed to getting this across the finish line. I can't say how important it is.
This interview has been condensed and edited for clarity.
Reference
- Endometriosis. at <https://www.who.int/news-room/fact-sheets/detail/endometriosis>
