Piraye Beim, PhD - New Developments in Predicting Diagnosis

Piraye Beim, PhD - New Developments in Predicting Diagnosis

Piraye Beim, PhD - New Developments in Predicting Diagnosis

Patient Awareness Day 2019: HEALTHY MIND & HAPPY PELVIS
Living Your Best Life With Endo
March 10, 2019 (8am - 5pm)
Einhorn Auditorium, Lenox Hill Hospital, New York City
https://www.endofound.org/patientday/2019

Good morning. I'm Piraye Beim. I'm the founder, CEO and chief scientist at Celmatix, which is a precision medicine company that's uniquely focused on women's health. As many of you in this room know or have experienced firsthand, it can take up to a decade before a woman with endometriosis receives a medical diagnosis. The Endometriosis Foundation of America is committed to changing this and has invited me here today to tell you a bit about my work with my company and also others that are accelerating the path to diagnosis. See if this works better for me today.

Before I get started though, as Karli mentioned, I should mention that my own diagnostic journey took nearly 20 years. In 2012, after nearly two decades of living myself with debilitating pain and experiencing about 18 months of infertility, I was diagnosed with endometriosis. It's a risk that I inherited from my family and also a risk that I know I've passed onto my daughter, so this is a very personal topic for me.

Unfortunately, my story is not unique. It's estimated that at least 10%, but possibly for this generation, up to 20% of the women around the world have endometriosis. That translates into over 176 million women worldwide. To give you a sense of scale, that's more than the populations of Russia, Japan, or Mexico. That also means there are more diagnosed cases of endometriosis in the US than adult asthma, Alzheimer's disease, rheumatoid arthritis or opioid addiction. In fact, every five seconds, a baby girl who will one day have endometriosis is born in the US. If we all went and lived in the same city, we would have twice the population of Los Angeles and nearly three times the population of Chicago.

Let's take a moment to discuss the symptoms that so many of you in this room are well aware of. I think Karli's introduction also resonates with us, which is that we hear a lot about the central role that pain plays, but what a lot of women and I certainly didn't realize is that endo also helps explain so much more than just pain. Things like chronic fatigue, urinary symptoms, Karli mentioned bowel symptoms, anxiety, depression, all of these have been attributed to endometriosis. We know it's a major cause of infertility and that up to half of women with the disease will have a difficult time getting pregnant. But, even more alarming is emerging evidence that endometriosis is also associated with a higher risk for ovarian cancer and things like cardiovascular disease further down the road. We're also starting to see endometriosis as a canary in the coal mine for other health conditions that will evolve later in life.

What's our current thinking on why these things occur in women with endometriosis? This is an illustration of the normal female reproductive system. Normally, endometrial tissue is a lining that grows inside the uterus, and the bleeding you experience during your period is when part of that lining is shed during your menstrual cycle. When endometrial-like tissue grows outside of the uterus, such as on the fallopian tubes, the ovaries, the body cavity; then a woman develops endomitosis. You guys saw the actual picture versions of this, but I'm showing you cartoons. Those pictures make me a little queasy. When endometriosis persists, then it can cause adhesions, which means that parts of your body can start to stick together, and also inflammation, which are thought to underlie the symptoms that you commonly experience, including pain.

As I mentioned, from the onset of symptoms, it can take a woman up to two years to ever make it to a doctor to have a conversation about her pain and symptoms, but it can take up to 10 years for her to get a definitive medical diagnosis. That's in part because the only definitive way to diagnose endometriosis right now is by performing pathology on samples that are extracted from surgery.

How do we fix this? How do we bring this disease into the 21st century? Right now, we know that we live in an era of technology. We use technology to solve so many problems in our life. I personally, part of what drives me from a mission perspective is that we should have the same level of technology to deal with something so fundamental and important as we do for how to find an ideal pair of shoes online that match our taste.

One of the problems that we have to solve with this technology is that every woman's endometriosis symptoms are a little different, so every woman with endometriosis is a little like her own snowflake. One of the challenges for scientists in the field is that in order to study this disease and for physicians, you have to lump it into different categories. Endometriosis is such a, what we call a heterogeneous condition, meaning every single person is a snowflake, that's really hard to study the disease.

One of the initiatives, or one of the things that we've been very excited by for those of us who look at the data, is that more and more women are starting to actually generate this data, so they track their cycles, including women with endometriosis, in order to manage their symptoms or to know when they're coming with apps like Glow, Flo, Clue, Ovia, and Natural Cycles. But, one of the challenges is that these data exist in the private sector, so these are private companies that have this data. It doesn't necessarily flow back into the academic setting where researchers can work with it. These apps haven't necessarily specifically been created to collect high-quality endometriosis-related symptoms, which we as scientists call phenotypes.

One of the initiatives that we've been very supportive of at The Endometriosis Foundation, and I think is really going to be transformational for the field is The Citizen Endo Project. If you guys don't know this, and you haven't downloaded the app, I highly recommend it. One of the nice things about this is that it was created by a researcher at Columbia University who actually has endometriosis and came at this is a computer scientist who said, "We just don't have good data." Until we understand how many different sub diseases we're working with here, it's hard to really be able to figure out how to diagnose it, how to treat it, et cetera. This app allows women to collect very detailed information about what they're experiencing. What was amazing for me the first time I sat down and learned about this app is that just in seeing the symptoms that you could track made me realize that again, so many of the things that I just thought were a unique part of my existence, we're actually part of this cluster of symptoms called endometriosis.

The other part of the equation isn't, so there's the phenotype side and the symptom side, but the other side of the equation is that we know that it runs in families, so Karli shared as well about how women in her family had undergone hysterectomies. For me, when I had my first really painful period, which was actually my first period when I was 14, I called my grandmother, and I talked to her about it and she said, "Oh, don't worry. That's a normal part of being a woman. We all go through that." That's one of the challenges is that because it runs in families and women are more likely to go first to a family member to talk about these things, then to go to a medical professional. They often hear that it's normal. That's a normal part of being a woman because that's all the women in their family have known as well. We know that it's hereditary, but we haven't really until recently, understood what underlies that hereditary nature. How is it that you can pass endometriosis on to family members?

One of the things that my company has done at Celmatix is that we wanted to get a sense of, so all of this academic research is being done some of it through NIH dollars, so your tax dollars, but what have we really found? We wanted to define from a data perspective, the landscape of how many different unique genes had been mapped as a risk factor for this condition. We leveraged AI to be able to go into the 24 million publications in the PubMed repository, and using computers, narrowed that down to about 4,500 published studies that have been done to date relating some genetic factor to endometriosis. Then, we also, using bioinformatics, mapped these, the genetic loci described in these papers to unique regions of the genome, and found that to date there have actually been over 600 genes that in some way have been linked to endometriosis risk. That just gives you a sense of how complex this is. Again, everyone is a snowflake. They're a snowflake genetically, they're a snowflake with respect to how they experience their endometriosis.

Then, we tried to rank how reliable these different associations were. Were different investigators in different populations around the world independently finding the same thing? Were these data holding up over time? We performed a kind of analysis called meta-analysis where we looked at that mathematically, and what we found at the end of that was as of today, there are about 12 different alterations, which means ways that you can change a gene in nine different genes that was a high degree of confidence, statistical significance increase a woman's risk of being diagnosed with endometriosis.

If we take a look at the different processes that these risk factors are involved in, it makes sense biologically, but also intuitively. These are factors related to how your blood circulates, these are factors related to how your body responds, to your immune system response to stimuli, steroidogenesis, which means how hormones are metabolized in your body, and then processes like tissue remodeling, cell proliferation, et Cetera, which all underlie the ability of tissue to really grow and thrive outside of its natural niche.

What we also learned was on an individual level, how strong each of these variants were. When you're defining the genetic landscape of a new disease area that hasn't really been well defined before, there are some conditions like trisomy 21, for example, having an extra copy of chromosome 21, that if you have it, you will definitively have Down syndrome. There's never been a human on earth who had that genetic feature who did not have Down syndrome. But, for things like endometriosis that are such complex diseases and have such an intricate genetic framework, usually just a single genetic factor on its own is not destiny. We wanted to get a sense of how strong these risk factors are. What we see on the right is something called an odds ratio, so that means if you had this, by what factor are your odds increased that you will develop the condition. What we see is that like many complex conditions, the odds ratios go anywhere from about 10% increased risk, which is like 1.1 OR, up to about 300% increased risk, which is OR 3.

For us, we felt that if we now had reliable markers that for example, put a woman at 300% increased risk of having endometriosis, that we thought that it was time that doctors start to bring these markers into the clinic, and the women start to empower themselves with this information. We launched a test called the Fertilome genetic test. It's the first multi-gene panel test for reproductive conditions like endometriosis. Currently, it's only available through fertility specialists, but we hope that one day these markers can make it upstream into the OB-GYN and be more accessible. We're also thinking about how we can go more directly to women, so that they can access this without having to go to a doctor maybe as one of the first steps of their journey, so we'll have some more updates on that soon.

What I'll tell you is that I was number 10, I was the Fertilome number 10, and what I found was that I tested positive for one of the highest effect markers, so one of the ones that fell into that highest category. Not only did I test positive, but I had inherited that altered gene from my mother and my father, which maybe explained why I had a much more difficult journey that my mother had had, for example. For me, even though I had the pain, I was a scientist, I saw the phenotype, I had met Dr. Seckin and he had said, "This is endo for sure," for me personally, seeing it on a genetic-test report and seeing that I also had this very high-risk marker ended up being what was catalytic for me to make a change and actually take some actions.

The other thing was that by understanding what this gene was and what it did, it helped me figure out what lifestyle modifications I could make. You were talking about gluten-free. One of the issues is that you hear about these things and it's a one size fits all, gluten-free doesn't impact me, but what I learned was that these alterations I had were in a gene that caused my body to be more prone to inflammation. What I found for me as a result of that is that acupuncture has been really transformational for me, also being very careful about my diet, alcohol, stress, the kinds of things that make you more proinflammatory anyway, have really been game-changing. I find that if I kind of fall off the wagon right before my period, have a lot of dessert, a glass of wine and allow myself to get super stressed out, I have a much more painful period that month than if I'm really disciplined. I've been able to kind of figure out my own body again by first understanding my genetics.

We found that I'm not alone. Over 76% of women who have taken the test, whose physician suspected that they had endometriosis, tested positive for one of these markers. We also have been working with Dr. Seckin and Dr. Goldstein to try to understand for women who come in for surgery, as well we see that a majority of them, that this was a very small pilot study that we did in its early days, have also tested positive for these high-effect markers.

But, risk is not disease. That's great. I'm excited that we now have one more tool in the toolbox to try to understand risk and it's an important part of the journey, but it doesn't, just because you have one of these risk factors doesn't mean that you're going to get endometriosis. A lot of women have these genetic risk factors, are passing them on, are born with them; but don't manifest the disease or have a much lighter version of the disease, so they may never be diagnosed. While a genetic panel, like the one that we developed, is an important part of the overall kind of progress that we're trying to make, it's not a true diagnostic. What else are people working on that I think are really exciting?

There's a company called DotLab, who you may have heard of, and they are using something called serum microRNA biomarkers, which means that ... What we look at, Celmatix, is kind of the hardware, so are you hardwired for a particular gene alteration, but then ultimately, that gene has to be translated and turned into something that goes and does an action in your body, so an RNA or a protein. What's exciting about what DotLab is trying to do is that they've identified some RNAs that get expressed and that you can pick up in saliva or blood that give you a sense of how inflamed your body is and whether you are, how your endometriosis is progressing. This is early days, but this test is available through an early access program, I believe. Again, I'm not affiliated with DotLab, but I think that DotLab and what they're trying to do to take it beyond just the risk is really important and really important next step of trying to have a true noninvasive diagnostic test for endometriosis.

The other area that I find very exciting as a scientist is the microbiome. As you may know, we are inhabited by billions and billions and trillions, kajillions of microbes. They live on our skin, they live in our organs, they live in our uterus. We're learning more and more that the composition of those microbes in and around your body are really important for your health, and your gut is a big area where you have a ton of microbes. We've seen some really interesting preliminary evidence that the microbiome plays an important role in endometriosis and therefore could also be an important set of markers to be able to identify either somebody who has endometriosis or how their endometriosis is progressing.

There's a company that, again, I'm not affiliated with, but I'm a big fan of which is uBiome. uBiome has generated one of the largest, I think maybe at this point, the largest microbiome data sets in the world. I was very excited when they launched a woman's health product called SmartJane. I think they're trying to now leverage the genetic signatures within the gut microbiome and other part of the vaginal microbiome to try to tell women things about their bodies, including hopefully, we'll have some interesting tools from them for endometriosis one day.

Then finally, there's a company called NextGen Jane, which again I'm not affiliated with, but have been following along. This is a screenshot from their patent application, but what their vision is is to have a tampon be a diagnostic tool. The idea's that there are so many different biomarkers in your menstrual blood and we should be able to identify many different things about a woman's health, including whether she has endometriosis from that tampon.

We're closer than ever. We're not there. I wish I was standing here saying great news, mission accomplished, but I do think that if I had given this talk last year even, we would not be as far along as we are now. Every year it gets more exciting. Hopefully, I'll get invited back next year to tell you where we are one year a further down the road. Thank you again for your time and I'm happy to take any questions if you guys want.