PATIENT AWARENESS DAY 2018: LIVING YOUR BEST LIFE WITH ENDO
Sunday, March 18, 2018, (8am-5pm) Einhorn Auditorium (131 E76th st) at Lenox Hill Hospital, NYC
Approaches to diagnosing, curing, and preventing endometriosis in the post-genomic era
Piraye Beim, Ph.D.
- So, thank you. So, I'm the founder and CEO of Celmatix as you explained, a next generation women's health company. And I just want to thank Dr. Seckin and everyone from the Endometriosis Foundation of America for the opportunity to share with you the work that my colleagues and I at Celmatix are doing to improve the diagnosis, treatment, and also hopefully prevention of reproduction conditions like endometriosis in the post genomic era. But first, let me back up and tell you about a revolution that's already happened in cancer. And this is really where the inspiration for the company came from. So the first human genome sequence was completed in 2001, and in less than two decades into this post genomic era cancer care has been completely transformed. So in the pre genomic era, cancer was diagnosed clinically and treated by targeting abnormal cell growth through surgical excision, radiation, and chemotherapy. But the problem is when you target cell growth using one of the biggest hammers that you have, you also do a lot of collateral damage to normal cells as well. And that of course means many serious side effects, which I think most of us who have known somebody who's gone through these types of treatments are familiar with. But thanks to advances in genomics, physicians are now able to zero specifically into what is disrupted in the particular cancer and treated in a much more precise way. Often with fewer side effects and better outcomes. This same genomic insight isn't just powering better diagnosis and treatment, but it's also helping identify who's at risk for cancer so that it can be prevented or caught much earlier in its progression. So now in comparison, where's women's health two decades into the post genomic revolution? Unfortunately, it's managed exactly the same way that it was during the pre genomic era, which is primarily through surgery and hormone therapies. This is true throughout a woman's life, from endometriosis to contraception, fertility treatments, and all the way through the menopause transition. And as with the pre genomic approaches to cancer treatment, targeting women's health conditions by taking the biggest hammer possible to the endocrine system results in a long list of side effects and sub optimal outcomes. Because virtually every cell in a women's body, from her skin to her bones are impacted by these interventions. So in 2009 I founded Celmatix, because in the era of big data and genomics, we can and we must do better for women. I founded Celmatix because I want more technology to be applied to helping a woman take proactive control of her reproductive health and fertility than is used to sell her a handbag on the internet. That feels like a pretty low bar, but we're not there yet. So what brings me here today is that if you care about women's health, and you're a women's health company, then you can't ignore endometriosis. So in the two minutes that I've been standing here, 24 baby girls who will grow up to experience this painful disease, were born somewhere in the world. That means that they will likely have painful and heavy periods, chronic fatigue, bowel and urinary symptoms, less pleasurable sex, and 12 of them will likely have difficulty conceiving. But it's not too late to change things for these babies, and my own baby girl who was born last year. We can and we must bring endometriosis into the 21st century. So how do we do that? What does this transformation require? Well, in short it requires better data, including genomics. These tools can help us take the first steps towards really understanding this complex disease. So let's start with what we know so far. So here's a typical woman's reproductive system. And in this slide, the endometrial tissue's where it's supposed to be, which is inside the uterus. So we know that in endometriosis endometrial tissue implants outside of the uterine lining. This can include on the fallopian tubes, the ovaries, and throughout the peritoneal cavity, and really beyond. The reason that hormone therapy works is because endometrial cells are dependent on estrogen for growth, and by controlling the levels of reproductive hormones in your body, you can help control the growth and activity of these cells. We also know that inflammation is another important aspect of endometriosis. But we're still in the process of trying to understand really the chicken and the egg with inflammation. So does inflammation cause endo, or does endo cause inflammation, or is it both? And then finally, in order to persist and thrive outside if its normal niche inside the uterus, endometriosis lesions must also find a way to evade the immune system. So how do these endometrial cells end up where they don't belong? The most popular explanation is retrograde menstruation, meaning that during your period some of the cells that are shred from your endometrial lining go backward through your fallopian tube instead of out through your cervix. It's believed that most women experience at least some retrograde menstruation. So why do some women get endo and others don't? Well, it's complex. And that's why we need to take a much more complex approach to this disease. In returning to genomics, understanding the unique genetic signatures that are present in women with endo verses women without is the beginning of bringing this complex condition into the 21st century. So at Celmatix, we've been working nearly a decade to really decode the genomics of endometriosis. So one of the approaches we've taken is to first get a handle on what other researchers have reported in the literature. So we use a combination of machine and human intelligence to create a complete catalog of every peer review publication that has looked at the genetics of endometriosis. And it turns out that there's more than 4,500 of them and counting. Next we read them all, and matched each genetic factor studied to unique locations on the human genome. What we learned through this approach is that over 600 genes have been linked in some way to endometriosis. Which is a big number, but not that surprising given what a complex disease it is. But what we know from cancer is that while for cancer too hundreds of genes are involved, there are a handful of master regulator genes that seem to be the biggest drivers of the disease. And also, that changes in these master regulator genes are the biggest risk factors for developing it. And so, next we set out to identify within these hundred of genes that had been linked to endometriosis which ones are really the master regulators. And what we found was that by ranking the effect that these genes had on endometriosis risk, we narrowed it down to nine genes that are most often significantly associated with the odds of being diagnosed with endo. And we also identified ten variants. In other words, ten ways that these genes can different in a woman with endo verses without. And we actually did the same analysis for all of the most common reproductive conditions in women, such as premature menopause, PCOS. And this work culminated in the markers that are screened for in our fertilome genetic test, which is the world's first multi gene panel test for risk of reproductive conditions in women. Another way that we've been revealing the genetic pathways that are involved in endometriosis is through understanding not just genetic sequence differences, but also through revealing what genes are turned on or off in an abnormal way in endometriosis. So here's another meta analysis that we did of existing data that was through other people's published work. And let me orient you on what these colors mean. So where you see red, that highlights genes that are expressed at a higher level. And blue are areas where genes are expressed at a lower level. And what you see at the top is a gene expression pattern for endometrial tissue that is inside the uterus, which we also call utopic tissue. The bottom is the gene expression pattern of endometrial tissues that's outside of the uterus. In other words, endometriosis lesions. Looking at these two images, you can tell that they're pretty different. But diving into the signatures of how these patterns change across the menstrual cycle, we also see that endometriosis cycles in an abnormal way. So what we see from this analysis is that just like the uterine tissue has a cycle, endometriosis has its own menstrual cycle, if you will. It's just a different cycle than utopic cycle. And so learning about this dysregulation can give us a guide. In addition to understanding how an endometriosis lesions are different than endometrial tissue in the uterus, this kind of analysis can also help us further zero in on these master regulator genes for endometriosis. Which is also the beginning of now moving the field away from only having hormones, so the biggest hammer that you can take at the system, as a target for therapeutic intervention and really start to just target the actual molecules that are disrupted in this disease. Ideally, in a way that wouldn't impact other tissues that you're not trying to impact outside of the endometrial lesions. So while mining data from existing studies has already started to help us make significant progress in transforming endo from a clinical disease to a molecular disease, we still need a lot more data. And so we've started to partner with leading academic and private fertility centers, and medical centers around the country to be able to put together data sets at the scale that we need to really start to bring this disease into the post genomic era. We're also grateful to the genetic testing company 23AndMe, who's also partnered with us on this ambitious work. One of the studies that we've done in collaboration with 23AndMe, is we've taken advantage of the fact that a large number of their customers also enroll in studies. So they want their genetic sequence to be used for good to really further disease conditions that are important. And so what we've been able to do with 23AndMe is we've been able to conduct the largest genome wide association study ever done to date looking at over 37,000 women with endometriosis, and comparing them to 251,000 women without it. Looking at 13 million genetic variations across the genome, we actually through the study were able to identify eight completely novel genetic regions of interest. So these are eight new genetic factors that had never been discovered before, even on that list of 600. And it just shows you that once you get to a sufficient scale, new signals start to pop out. And this work will be published together with the IEGC, the International Endometriosis Genomics Consortium later this year. In addition to mining the data in 23AndMe's existing community, we also partnered with them to launch a really landmark fertility study. So we recruited 4,500 women who either were actively trying to conceive, or were already pregnant. And we've been tracking them now, we're tracking them for 18 months perspectively. We're about halfway through the study, and we're looking at if they have endometriosis, who gets pregnant, who has a miscarriage, who ends up with a pregnancy complication. We're also tracking microbion signatures in these women. We're tracking, in addition we have access to, in some cases, their partners information as well. We know what drugs they're taking. We know if they're jet lagged. We know if they're doing acupuncture. And so in the cancer world, the government funded these huge ambitious studies. And so you could create those data sets. Unfortunately, very little funding goes into this kind of research in women's health. And so we're very proud to be partnered with 23AndMe to be generating this landmark data set to really try to understand that intersection between genomics, lifestyle, diet, environment, et cetera, in both fertility and in reproductive outcomes through pregnancy. But big data is more than just having big amounts of data. You have to also structure it and get it to talk to other data to make it useful. So if you have clinical data but it's not linked to genetic information, that's not as useful. And if you have genetic information but you don't really have it annotated, that's not as useful. And so what we've been doing is another platform that we've really invested a lot in brings the data from all these studies in our network together in a common platform that we call the reproductive atlas. Reproductive atlas is really what we call learning, it's the core engine of a learning health system. So in a learning health system you make a hypothesis. You then test it clinically. You see the outcomes, you refine, and you make another hypothesis. And so we're really proud to have brought all of these studies and this data together in this way. And so we're getting closer to saying that finally women's health is in the post genomic era. And again, we can't do it alone. One of the things that we found out when we were studying these thousands of women across the country is that even though we live in an era when so many differences, sexual orientation, gender, et cetera, they've come out of the closet, they've become very accepted. Unfortunately, fertility and really a lot of things about women and women's health are still in the closet. And so we found that half of women who had had a miscarriage had never talked to their friends about it. We found that actually one in five women who had had a miscarriage had not even told their partner. We found that the majority of women who were thinking about fertility treatment or going through it hadn't told anybody that they were going through it. We found that one in four women who were trying to conceive had not even talked to their doctor about it. So what we found was that there's still a lot of silence. Not just around endometriosis, but really every aspect. And so we started a campaign called Say the F Word for fertility. And we're proud to be partnered not just with great other mission driven companies like Celmatix that really care about bringing these things into the light, but we're also proud to be supporting the Endometriosis Foundation of America. And if you go to our website and you pledge to join us, and to say the F word in 2018 with us, we'll donate to Endometriosis Foundation. So thank you.