This week I am talking to Maneesh Jain, PhD CEO of Mirvie (@mirviedx) that is bringing a level of personalization and safety to pregnancy with a revolutionary approach.
Maneesh has an interesting back story that started as we unraveled the human genome and shares some important insights about that early work and the over-promised potential that was celebrated, but as he points out we had one, just one human genome sequenced.
We discuss the declining state of maternal health in this country of diseases and conditions that the vast majority are preventable yet we fail to catch them. As he shares
80 of pregnancy-related deaths are preventable.
We dive into the science of sequencing and the specific use case that looks at mRNA. In their research (RNA profiles reveal signatures of future health and disease in pregnancy and LB 2: Early prediction of spontaneous preterm birth in a high-risk population using cfRNA profiling) they detail the ability to clearly identify future health problems in pregnancy some 3 months before they are clinically detectable in the mother.
Listen in to hear what mothers’ perspective is on having this information and the amazing opportunities that lie ahead as we learn to apply this technology to other areas
Listen live at 4:00 AM, 12:00 Noon, or 8:00 PM ET, Monday through Friday for the next week at HealthcareNOW Radio. After that, you can listen on demand (See podcast information below.) Join the conversation on Twitter at #TheIncrementalist.
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Raw Transcript
Nick van Terheyden
And today, I’m delighted to be joined by Manish Jain. He is the CEO of mervi. MANISH thanks for joining me.
Maneesh Jain
Thank you, Eric. Pleasure to be here.
Nick van Terheyden
So as I do with all my guests, I like to get a little bit of background perspective, especially, you know, as we talk about the area of focus here, so if you would share a little bit of your journey to this point in your career and how you arrived here.
Maneesh Jain
Yeah, so I’m a scientist by training. And 20 years ago, I got quite fascinated by what was in the early stages of the Human Genome Project. Because it seemed like the first time we were going to start to understand the underlying basis of human biology, and potentially be able to treat diseases and conditions. So that was the beginning of my journey, I was very fascinated by how we could take the science and bring it to practical applications that could impact people’s lives. And so that’s led me in an entrepreneurial journey, in the last 20 years to build several companies that have developed products in the sequencing space, and the applications in oncology. And most recently, pregnancy health. I think if we look back at the revolutions in the last decades, that we’ve had in tech, that’s been really facilitating an understanding of inflammation and how that moves. And for us, we still lack this fundamental understanding of how our biology works. And so to be at the doorstep of being able to understand that and use that for benefit was just very compelling for me. And that’s the story of my career.
Nick van Terheyden
Interesting. So before we dive in, I think it’s worth sort of spending a little bit of time since you’ve been in that space, and, you know, focused on that path. And, you know, and my recollection of the Genome Project, particularly as we sort of got to the point of, you know, the full sequence we have this, you know, took billions of dollars, and, you know, all the cost issues separate but from a content and science understanding perspective, one of the things that I recall very strongly at the time was, we found it, but 95% of it is junk. Do you remember that? Do you have a recollection of how you sort of perceive that, you know, as you were in this space?
Maneesh Jain
Yes, definitely. And there was many quips about it. I think a lot of people said at some point that those who call it junk DNA are junk scientists.
Nick van Terheyden
I have not heard that. But that’s I’m sad, because I think a lot of us did, because we didn’t we just follow the crowd. But keep going. I’m sorry.
Maneesh Jain
Yes, yes. So well, what was interesting is I think we learned how much we don’t know, in the early days. And so the human genome, the first Blueprint was supposed to unravel all of disease. And that turned out to just tell us well, that’s just what we have a blueprint for one person. So how is each person different. And so we continued on that journey. I think it’s truly the century of biology. And so it’s not one project, or you know, a space of one decade that it’s going to unravel the complexity of human biology. But I think you can just start to see the advances we’ve made in the last few decades. So I think take them college, you, for example, you know, in the early 90s, it was chemo for every cancer. And that’s just what it was. And then we started to understand starting with breast cancer, that well actually, that condition has multiple subtypes. And those are molecular subtypes. And each one should be treated quite differently. So today, when you get diagnosed, if you’re unfortunate to be diagnosed with breast cancer, fortunately, there are very powerful tools that tell you what type of breast cancer it is, and tailor the treatment according to that molecular condition. And I think that’s a major advance, we’ve been able to make other major advances in infectious disease, but vaccines and a lot of the mRNA vaccines recently. So our focus is really to try to apply some of the same tools to expand the knowledge base in pregnancy health. So surprisingly, if we look back a few years in 2018, when we started, maybe, we realized that it was really a big black box. And it is so today, but I think there’s the opportunity to illuminate that. How does pregnancy development happen? What is development of normal pregnancy? And what where do we go off course sometimes to more complicated pregnancies conditions like preterm birth and preeclampsia. So I think I think the bigger picture, you’re just at the doorstep of starting to understand this. And it might take us some decades to really fully unravel all of biology, but I think there are very powerful tools now in the Human Genome Project, and those technologies that kind of allow us to read biology and convert it to digital form. And then the other set of powerful technologies like machine learning that allow us to take that digital information and make sense out of that. Find patterns.
Nick van Terheyden
Yeah, so there’s a lot to to unpack there. You know, not least of all your point. I extremely eloquently stated that, you know, when we sequenced one genome, we had one genome, but there was all this uproar about, wow, we’ve got a genome, but of course, nothing to compare it to, which I think is one of the most important points. And obviously, the cost and the decline in, you know, processing needs allows us to get to more of it, you know, opens up the doors. What are the things that I would suggest, you know, you talk decades, my hope is, I think, a little bit faster than that just based on the recent pandemic, where we really push the extremes of this processing that I think will maybe speed things up. One of the key things that I think is important to understand and, you know, relates back to this sort of junk DNA concept, we’ve understood now that that impacts that the expression of genes, and I know we’re gonna dive into, you know, what mervi does and how we do it. Let’s understand that first, because I think there’s, you know, some important points relative to that. So would you explain what Nervi is and how it works?
Maneesh Jain
Yes, definitely. I think for every field, there is a point in time where, where it’s ready for breakthrough, or to really change the status quo. And we really believe that pregnancy health and maternal health is there today. Partly because I think this era of declining maternal health has come to a head. And if you look at the news that’s been out there with preventable 80% of maternal deaths are preventable. That’s some information from the CDC could look at the last 15 years, we have doubled the rate of hypertensive or blood pressure disorders in pregnancy. So some of these things are really coming to a head in the area, which is not just a point in time, but impacts, certainly the whole lifetime for the baby, and a large part of the lifetime for the moms. So if you talk about lifetime impact of disease, this may be one of the areas that has the greatest lifetime impact. So it really compelled us to try to see what we could do urgently in this area. So some of the tools that have been applied in the oncology space are looking at genome wide patterns of changes, that could be predictive of disease. And the way you do that is, thankfully, through the declining costs in genome sequencing, we’re able to look at a lot of sequencing data for many individuals. And it’s that combination of comprehensive view of what’s happening in the biology across 1000s, and 1000s of individuals, that ultimately gives you a power to find reliable patterns. And so what we’re doing is really using the Mirai RNA platform, this is something that was developed at Stanford and Steve squeak lab over over Steve quakes lab over many years. It’s the first time that we’re able to actually start to look at the underlying biology. And so what happens is, as you have the developmental processes in pregnancy, there’s a lot of changes in the uterus, the cervix, the placenta, and of course, the fetus. And so the combination of that molecular signature is really the RNA messages that are changing and being communicated back and forth. So we take a simple blood sample from the mom. And through that simple blood sample, we’re able to tap in to this changing biology, and to find patterns that are indicative of a normal pregnancy progression. And then other aberrant patterns that are indicative of potential complications to come. And the really exciting thing is that you’re able to do this about three months in advance of the symptoms. And so today’s standard of care has really been driven by symptoms presenting themselves, and then the physician doing the best they can, often in the crisis mode, like if the baby is going to be born preterm. But imagine if you could identify these symptoms, and signs, sorry, not symptoms, but the underlying biological science, three months in advance now for the first time, you can start to take preventive steps and try to make a plan, treat the condition and hopefully prevent them. And so that’s really a big step forward in the field to be able to do that approach. And it’s only possible because we can start to tap into the underlying biology early in pregnancy.
Nick van Terheyden
So I think it’s important before we sort of dive into some of the benefits, to separate out some of the science because I think people get confused. When we talk sequencing, I think, for the general understanding, it’s, oh, I’m going to sequence you so I get your DNA. And you’re actually talking about something different and that’s where it’s important because some of this expression of genes is where this is actually demonstrated in the body and you’re picking up those signals. And I think this is important to understand. So make sure that what I’m I’m saying is correct. So when you take these samples from the mothers, you’re not sequencing the DNA, which, you know, people get confused and say, well, am I am I a product of my jeans? So it’s a no choice, no problem. This is something slightly different. You’re looking at a different element. Can you explain that?
Maneesh Jain
Yeah, it’s, it’s very different. And thank you for bringing that up. So DNA is what you have for my mom and dad. And by and large, just not changing in every cell of your body and throughout your lifetime, it’s static, it is helpful for certain things in pregnancy. So in the last 10 years, we’ve been able to have these non invasive prenatal tests that look at changes in chromosomes. So if chromosome 21, for instance, you have three copies instead of two copies, then you get down your baby has Down syndrome. And so that’s something we’ve been able to test from just a blood sample. But those conditions are what we call genetic. And there’s not much you can do about them. They’re just present in your DNA. So they’re static. And it’s essentially, you have what you have, what we’re doing is something very different. We’re looking at RNA. So what is RNA? Well, if you have the same DNA throughout your body, how is any organ different from the other organ? And how are you aging? And how are things changing throughout your lifetime, because the DNA is the DNA? Well, the most important difference is the DNA gets converted to RNA. And that is very different in every cell. And it’s very different at every point in time. And so the whole dynamic nature of our life, the development of tissues, and all the changes to our lifetime, are really mediated through RNA. So you start with the same DNA blueprint, but it gets converted to different levels of different genes expressed at different points in time. And that’s really what drives all our biological development. And so in pregnancy, you might imagine that there’s a pretty, it’s probably the period of most rapid development for human beings. And so it is, of course, then mediated by these RNA changes. And each pregnancy is different. So you could have the same parents. So theoretically, very similar DNA, but the RNA, as it’s expressed, can be very different and be different at different points in time. So that’s really what we’re tapping into is these RNA changes. Now, one of the most exciting things, of course, is that because it’s not static, it’s dynamic, you could potentially understand the underlying biology and then try to prevent the conditions because it’s not static. So just like it’s off going off course, you could potentially correct it. And a lot of the work that has happened in the field with RNA based Therapeutics is very promising. So I think that’s what’s very interesting about this area, it’s really a new frontier, where we’re looking at the dynamic changes that lead to the disease course, and the potential of having precision medicine to try to tackle that and prevent it.
Nick van Terheyden
So for those of you just joining, I’m Dr. Nick, the incriminated incrementalist. And today I’m talking to Manish Jain, he is the CEO of mervi, we were just talking about the differences between DNA, RNA messenger RNA and you know, the enormous progress that’s taken place in terms of sequencing, which is not just about that sort of static sequence of your genome. But actually the expression of that and the way that it’s expressed. And I think if I sort of encapsulate what you just described, no matter what’s going on, you have multiple different expressions of messenger RNA that you’re able to measure as part of this whole process. And it’s that information that mervi is now sort of taken, and is offering some insight that I think is quite extraordinary, right? So tell us what you did. And you know what you’re starting to see.
Maneesh Jain
Yeah. So one of the first things we did was to make sure you can actually measure RNA reliably, because it is it is new technology. And it’s it’s more subtle than DNA. And that’s why the development has taken, you know, about a decade longer than it did for DNA. So the way we did that is, of course, do a lot of work in the lab, but then very quickly start to test on on samples, blood samples that were collected retrospectively, through collaborations with many academic medical centers. And that really then started to establish that we could reliably detect RNA. So we published a paper in Nature earlier this year in January 22. And one of the main things that showed was that for normal pregnancies, there were predictable patterns of RNA. So what that means is, we looked at 1000s of women. In fact, I believe that study was about 2500 samples from women across the world, eight sites in the US, a couple in Europe and one in Africa. So we wanted to make sure these studies are very diverse. So the results are broadly applicable. And what that showed us is that In fact, the RNA changed very predictably in the course of normal pregnancy, meaning that we could take a blood sample at a certain point in time. And just by looking at the RNA from the blood sample, we could date the pregnancy, how far you are in the pregnancy. So that’s pretty remarkable. That’s very comforting, because it shows us that there is a baseline patterns that that determines the development of the baby and the changes for the mom. So now you can start to ask the question, okay, if there are deviations from that pattern was that mean? And so one of the things we showed in that same paper was if you took samples from moms who went on to develop preeclampsia three months later, and compare them to blood sample from moms who had a normal pregnancy, we found a specific gene patterns that were distinct and different in those moms who went on to develop preeclampsia. So one might call that a signature for preeclampsia. And then we went on later in the year to do a study, again with hundreds of them and then showed the same thing was possible for preterm birth. So premature birth is when the baby is born before 37 weeks of gestation. And really fascinating in that particular paper in the age dog, or so called gray journal was that we could distinguish between the patterns that for very early preterm birth and versus early preterm birth. And so even within a condition, this is very exciting, even within the condition that historically has just meant the baby is born early, it has not meant due to what reason, now, we are starting to unravel a little bit of that biology, because I think the belief in the field, most experts in the fields believe that we will be a time soon, where we can take a condition like preterm birth or preeclampsia, and identify it by their molecular subtypes. So you might be able to treat them differentially. It’s very analogous to what happened in the 1990s with breast cancer, right, it was one disease, one condition. And then we started to figure out, oh, it’s actually two or three different conditions that can be treated quite differently, and much more effectively. So we’re not there yet. But we are on the doorstep of starting to find that level of resolution of some of the major complications in pregnancy.
Nick van Terheyden
You know, I think, great description of that, I think very helpful in terms of understanding one of the, you know, key points that sort of arises in my mind about all of this, and it was true with oncology, I think we’re going to have to develop a whole new terminology, or methodology to categorize disease, because we’ve gone based on location in the body, which actually is starting to make less and less sense, it’s more at this molecular last level. You know, I’m just in the process of reading the song of the cell book by Siddharth Mukherjee, which, you know, is exposing a lot of this in the oncology space amongst others. extraordinarily exciting, and you talk about three months ahead of time. So there’s obviously some point in the pregnancy where you say this is maybe the optimum, or maybe this is a measurement that takes place sequentially. That gives you those biomarkers, the extraordinary point here is that now you’ve got some opportunity for early intervention, which is saving money. It’s better for everybody, you know, that just awful statistic that you cited at the beginning, you know, this enormous maternal deaths, you know, poor outcomes, we can actually head off, and that’s in the US to be you think about this elsewhere. There’s huge. Tell us a little bit about how this is enacted and how we get this, you know, distributed out?
Maneesh Jain
Yeah, so we’re still in the development stage, I think, we feel, I think, an urgency to try to get this to market as soon as possible. But I think also the responsibility to do the most rigorous science, because it is such an enormous potential impact. And so we’re doing a very large clinical study with 1000s of women collected all across multicenter trial, very diverse study across the US. And the idea of that is to just validate some of the findings that we have discovered to date. And once we do that formal clinical validation, then we’ll be ready to bring this to market. I think what’s very interesting is this taking the physicians perspective, and the moms perspective and this approach, you know, physicians are doing the best they can, right, but they’re limited today in two ways. One is, they don’t have the tools to be able to predict disease. It’s really been very symptom driven throughout the decades. In fact, I think some of the things are surprising, but makes sense in context. So the current prenatal visit paradigm, the 12 to 14 visits is from the 1930s. And it hasn’t changed. And the reason there’s fewer visits early on, and many more visits towards the end is the symptoms of conditions like preeclampsia often showed up later in pregnancy and so they wanted to come Extra symptoms. But yet, it’s really the blood pressure measurement or the symptomatic measurement is really in those few visits, you know, a week or two apart, it’s not real time. And so I think that’s a big shift, that would be very welcome to physicians to have a tool. The other thing is, it’s really not possible to educate everybody on everything that can happen in pregnancy, because it’s a long list. And it’s a time where it can be an overwhelming time for families. But if you knew somebody who was at risk, for one condition, you could certainly go much deeper in educating on that particular condition. So they would be aware of the signs and symptoms. So for instance, in our survey, it’s really, this was the survey of 1000 women, nearly pregnant or had been through pregnancy recently 91% that they wanted more information about the pregnancy, and about the risk of developing conditions. And that there was this would really help them make a better plan, rather than just causing anxiety, because that’s been one of the historical kind of concerns like, Well, is it just going to cause unnecessary anxiety and most moms 91% Say that it’ll actually help them make a better plan. The other thing that’s very interesting is, I think a large majority of women said they understood the signs and symptoms of preeclampsia. But if you actually go through what the signs and symptoms are, it’s only 9% Who can identify every single one of them. And so this just speaks to the education gap. Because again, you can’t educate everybody on everything. But if you knew you were at risk, for one condition, you could certainly go quite deep and make sure they understand a lot more about that. Yeah, yeah,
Nick van Terheyden
it clearly exciting opportunity. But there’s still some work to do, you know, lots of respect for you, you know, focusing on making sure that the science is right, I think you don’t want to get this wrong, you want it to roll out, but you’re talking about a change in the prenatal sequencing at this point. And that’s a poor choice of words, because you think DNA, I’m talking timing, yes, of appointments. And, you know, so big changes that would contribute to essentially, I’m going to call them biomarkers for a sort of generic term that would allow you to sort of guide care, in a very broad sense across, essentially everybody with a simple blood test. Is that true? Is that where you see this going?
Maneesh Jain
That’s right, yeah, we see this as a change in standard of care. So very quickly, I think, just through the COVID area, like in many areas of medicine, there has been a revisiting of this 12 to 14 in person visits, to have a combination of in person and remote. So that’s it’s great to see the field evolving. During necessity, I think what this would do is give you another tool, very powerful tool, where the disease biology that often starts in the first trimester, we can measure early in the second trimester, and give you that sort of three months advance notice before any symptoms to try to prevent them. So yes, it would become a pretty powerful tool that we see as a standard of care, new standard of care, that would allow you for the first time to go from kind of reactive symptom based medicine to much more proactive and preventive medicine.
Nick van Terheyden
And, you know, I know it’s hard at this point, you’ve obviously got two extremely important markers. I imagine that there’s potential for much more than that, in the future, as you sort of gather more data and analyze more sort of outcomes. Is that a fair assessment?
Maneesh Jain
Yes, there’s, I think, so many of these conditions that we have to address. So we talked about preterm birth and preeclampsia. But there’s also growth restriction of the baby, there are several placental mediated disorders. And then there’s also gestational diabetes. And all of that is still just looking within pregnancy. So if we look a little beyond that, we know that some of these conditions create a lifetime risk of cardiovascular disease and stroke for the mom, and developmental disorders for the for the baby. So beyond pregnancy, we could actually then start to look at some of these markers, which are potentially predictive of what’s going to happen later in the lifetime. And then imagine if you could start to prevent some of those conditions that would really change dramatically, I think the lives of many people,
Nick van Terheyden
I think, really exciting times, you know, tremendous opportunity. I’m, you know, hopeful that we can accelerate this through the process of science go through the appropriate measurements, but all of this opportunity, not just within pregnancy, but the expansion of this capability is really going to change the way that we sort of interact with our patients. And I think ultimately changed the grammar and the vocabulary that we use in medicine. So exciting times, unfortunately, as we do each and every week. We’ve run out of time just remains for me to thank you for joining me on the show man each. Thanks for joining me.
Maneesh Jain
Thank you, Nick. Appreciate the opportunity.
