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MSU researcher working to learn how embryos interact with the maternal environment

Russ White
Ripla Arora

Ripla Arora is an assistant professor in the Department of Obstetrics, Gynecology, and Reproductive Biology within the College of Human Medicine and is the Chief of the Division of Developmental and Stem Cell Biology in the Institute for Quantitative Health Science and Engineering. Her research focuses on embryo uterine interactions at the time of implantation and uterine development.

Russ White:Ripla Arora is my guest. She's an Assistant Professor in the Department of Obstetrics, Gynecology, and Reproductive Biology within the College of Human Medicine at MSU, and she's the Chief of the Division of Developmental and Stem Cell Biology in the Institute for Quantitative Health Science and Engineering, better known as IQ. Her research focuses on embryo uterine interactions at the time of implantation and uterine development. Ripla, welcome to the show.

Ripla Arora:Thank you, Russ, and I'm so glad to be here and so glad to meet you.

White:Tell us what happens in the Arora Lab, what does your research entail? 

Arora:We're primarily interested in understanding how the embryos interact with the maternal environment to find an ideal space for attachment. And then we're interested in how the three dimensional structure of the mother guides the embryo to find a good site for attachment. And most importantly, what happens when this embryo ends up in a less than ideal space. How does it affect the pregnancy, the fetal growth, and how does that cause poor pregnancy outcomes? The basic idea in our lab is that the embryo forms from the sperm and the egg as a single cell and then undergoes multiple rounds of divisions to form a structure called the blastocyst which is what is going to attach to the maternal structure. At this stage of development, the embryo is about 100 micrometers in dimension. Scientists have developed really amazing methodologies to image this tiny embryo. And it also helps that the embryo is quite transparent at this stage so it helps in the imaging process.

While the embryo is dividing at these early stages, it is not sitting still. It is actually moving through the maternal structure, the fallopian tubes, the uterus, and it's trying to find a good site for attachment. And the question that we are really interested in and the real gap in knowledge is what is the maternal structure doing at this time? Is it static? For example in the mice, the uterine horn is a tube. We're interested in knowing is the tube open? Is the embryo floating in it? How does it know where to go? But in order to answer this question, we had to first develop a method to visualize the structure of the uterus in three dimensions which would also allow us to visualize the embryo. Now this is very tricky because in the mouse, the uterine horn is 1.5 millimeters thick, that's 1,500 microns, and the embryo, as I said, is only about 100 microns. We needed to develop techniques such that we could image structures that were 15 fold different but clearly identified structures for both of them.

This is what we did. And we have achieved this in fixed tissue. We can do a time series of the embryo changing its location along the uterine tube and we notice drastic changes in the structure of the uterus which facilitates the movement of the embryo to the ideal place of attachment.

White:So, Ripla, how mature is this research? What are some benefits to society your research can lead to? And how long might that be?

Arora:The two main discoveries that we have made so far are that the uterine tube folds, but it folds very specifically in response to ovarian hormones when there is a pregnancy coming in. The second thing we learned is that it's already known that every mammal has uterine glands. These glands take care of the embryo until you form a placenta because mammals don't have yolk. Something has to nourish the embryo while you're waiting to form the placental structure. Everybody knows those are the uterine glands. But what we don't know is what do these glands do? Structurally, for us we are interested in structure, How do they connect to the embryo? Do they directly contact the embryo? Do they secrete the material in some luminal space that arrives to the embryo?

I want to tell you a historical anecdote. In earliest times when cadaveric dissections were not allowed or permitted by the church, one had to really guess either based on outward appearances or philosophy or animal studies. The hypothesis was that the uterus has a bunch of suckers that line the uterine lining and that's where the embryos get stuck and they live and they grow. But they also thought that the uterus is connected to the breast so that whatever feeds the baby in the uterus when the baby is born, it gets the same feed from the breasts. And that's why every time you see very olden drawings of female anatomy, the breast is always connected to the uterus.

Now, you know, microscopy has happened. We can image the embryo. We are starting to image the uterus, but we still don't know very well how are the glands connected to the embryo? How are the secretions getting to the embryo? I think we have taken the first step where we have found that these glands actually conglomerate around the embryonic attachment site and we think that this is going to be very important for the glands to actually access the embryo and directly give secretions that are important for the growth of the embryo. And you can never visualize something like this in two dimensions.

In terms of what is the impact of our research, my vision is that the methodology that we have developed will transform the way we view the attachment implantation process. There is a lot of amazing work, like I said, about embryo development. There's also a lot of basic molecular and signaling knowledge on how the hormones from the ovary and proteins and other signaling pathways are absolutely critical for establishing a healthy pregnancy. We want to add a layer of information pertaining to uterine structure and connected to the cellular mechanisms that affect pregnancy. This will lead to a better understanding of the conversation between the fetus and the maternal lining, ultimately improving our approaches in the clinic. We think our work can help improve the outcomes of, for example, artificial reproductive technologies, it can lead to novel approaches for treatment of infertility and also identify non-hormonal targets for contraception.

I want to give you one specific example of how our work could be relevant in the clinic. In artificial reproductive technologies, women undergo a process of hyperstimulation with hormones. Basically, we want to stimulate the ovaries so we can have many eggs. Normally, in women, there's only one egg produced per monthly cycle. But now when a woman goes into the procedure for IVF, you don't want her to go through that procedure over and over again because it's quite a painful and complicated procedure. So we hyperstimulate the women so we can retrieve multiple eggs at the same time, do in-vitro fertilization so that the chances of getting a nice, fertilized embryo is good, high, and then we can put this embryo back into the uterus. But what we don't know is, when you hyperstimulate, how are you affecting the structure of the uterus?

We know that the rate of attachment of the embryo, if you do IVF and put it back in, is much lower than the naturally conceived pregnancy. We believe part of the reason that this happens is the structure when we put the embryo back in is not ideal. Because we don't know what is an ideal structure. What is the timing? When is that ideal structure coming to be? And how do these excess doses of hormones change or manipulate that structure?

We think that if we understand the structure better and if we understand this kind of groove that the embryo absolutely needs to attach, the rate of attachment and the rate of a successful pregnancy will be higher. We really hope that the data that we are collecting using initially mouse as a model, and we're also trying to push this technique in primates, will actually assist us in identifying what a good structure is and what a good site of attachment is.

White:Tell me more about what's next, then, in the Arora Lab as you advance this.

Arora:There are two main larger focuses that are specifically applicable to humanity. One is that, as I said, understanding the embryo movement is absolutely important. And then the second thing is pushing the envelope in these imaging technologies so that we can really figure out the structure of more complex uteri. That's the goal. As far as the embryo is concerned, I said we do it in fixed tissue. What we really want to do is to live image the movement of the embryo because as long as it's a mammal, even if you are a mouse, even if you are a guinea pig or a rabbit or a primate, the movement of the embryo has to be very specific guided to find a good site of attachment. So these are our big goals, our dream goals to achieve which we think will really influence the field of reproductive biology.

White:And, Ripla Arora, you're part of Chris Contag's precision health focused IQ team we talked about before. Talk about this collaborative breaking down barriers science setting that Chris is developing and what excites you about it.

Arora:I was recruited to MSU as a part of, as you said, the OB-GYN department and IQ. Really, I'm so thrilled to be here because there are some amazing reproductive biologists. The OB-GYN department at MSU is one of the best. IQ is at the cutting edge of imaging technologies. I work on developing imaging technologies for reproductive biology. I think this is a really good fit for me. I think that the biggest thing, and I think other people who have been on this podcast have also said that is, sometimes I think about an experiment which is completely crazy. But then I find someone on the floor above me who can help me achieve that crazy. Really, you can do incremental science. Add one plus one, and then another one, and then another one. But you really get amazing discoveries when you have exponential growth. That usually happens when you're thinking outside the box. If you're in your niche of individualistic field and you're not at the interface of multiple different fields, you're slower in getting to where you want to be. I mean, you can collaborate, but this makes collaboration really easy.

I meet all these faculty and I really, as I said, I want to develop these imaging technologies. But IQ is the place to be to develop the kind of imaging technologies and to think about newer approaches that we could develop to understand the structure. And in addition to imaging, I would also say IQ has the bandwidth to do a lot of computational work. That is another side I want to develop in my lab which is quantitative modeling. The way I see science going from now is that you have a biological problem, you do an experiment, you get some results, you figure out what they mean quantitatively, and you create or make a predictive model that, "Okay, if this is really true based on quantitative or mathematical modeling, this X, Y, Z should also be true." Then you go back to the bench and do the biological experiment and you get some more data. So you keep going back and forth until you have completely broken down the process. That's what I want to do.

White:Tell me some more about how your work benefits from this interface of medicine and engineering.

Arora:My training is as a biochemist and as a developmental geneticist. What that means is that I work with developing embryos in the mice and I study how genes affect the development of structures. And then in my post-doctoral work is when I realized that I need to couple this with some quantitative mathematical aspects. That's where we are going with this. I think engineering, for example, I'll give you a very simple example is that we work on the uterine structure. Right now we're trying to see, "Well, how can we remove the uterus from the mouse and how can we keep it alive in a dish?" Sure, you can have all these beautiful signaling factors that are going to keep it alive, but we realized that unless we can keep the uterus in its native structure that exists in the mouse, we can't really do anything with it because it collapses on itself and it dies after a few days.

But then we go to the engineers and we're like, "All right. Can you help us figure this out? This is what it looks like in the mouse. You're the engineer. Engineer us something that we can use in a dish," and then our uterus is going to mimic more how of it looks in vivo. And that's the idea behind it. Definitely, I really strongly believe, and that's what I teach my students, that mathematics and quantitation is going to be the absolute next step for the validation of your biology.

White:As you mentioned the students, how do we make sure they're trained in this new collaborative spirit? Or are they all just coming up this way now?

Arora:I think in this age of technology and social media where the world is collapsing into a much smaller space, the students’ thought processes are more diverse than I would say mine used to be. The only constant thing is change. Even in biology, the techniques we use today are very different from the techniques I used when I was a graduate student. I think the only way to do good science is to combine the classical techniques, for example in embryology, with these amazing new techniques, for example the confocal imaging with high resolution analysis. I think the young generation is very smart. They learn from watching. If they see us as mentors trying to learn and be at the interface of all these different fields, it motivates them to do the same. I think that the way to train the next generation is by showing them. They absorb what you teach them, and that's what makes them really excited to tackle the next set of research questions.

White:Ripla, as we close then, summarize your work and what would you like us to know about it?

Arora:I think imaging is amazing. You know how they say, "A picture is worth a thousand words?" I'm going to say a 3D picture is, what, a million? And a 3D movie has got to be more than that. I think that imaging and quantitative biology is the future. I actually don't think it's the future, it's the present, and it's going to build the future. We're working really hard to combine all of these skills to address very basic questions for developmental biology, but also with a larger goal or a long term goal that whatever we produce in our model systems will be applicable to understand the concept of infertility and will give hope to these women who, for decades, have had these questions but not enough answers.

White:Well, Ripla, thank you for telling me about your work and all the best on your research endeavors moving forward.

Arora:Thanks, Russ. It was great being here.

White:That's Ripla Arora. She's an Assistant Professor in the Department of Obstetrics, Gynecology and Reproductive Biology within the College of Human Medicine at MSU. She's the Chief of the Division of Developmental and Stem Cell Biology in the Institute for Quantitative Health Science and Engineering, better known as IQ. And there's much more online at iq.msu.edu.

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