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Geneticist Gabrielle Kardon, Ph.D., never thought…
Date Recorded
May 19, 2015 Science Topics
Health Sciences Transcription
Interviewer: Stepping out of the Ivory Tower and into the arms of the patient community. Up next on The Scope.
Announcer: Examining the latest research and telling you about the latest breakthroughs. The Science and Research Show is on The Scope.
Interviewer: I'm talking with Dr. Gabrielle Kardon, Associate Professor of Human Genetics at the University of Utah. Dr. Kardon you were in Washington D.C. last week, what were you doing there?
Dr. Kardon: The purpose of the whole trip to D.C. was to go with these families who are all affected by congenital diaphragmatic hernias. So this is a common birth defect that affects about 1 in 3,000 children, and to rally support from the House and Senate for increased funding for NIH, in particular for birth defects and CDH.
Interviewer: Could you have imagined doing this a year ago?
Dr. Kardon: Well maybe a year ago, but five years ago I wouldn't have. What we were able to find is that the connective tissue, which is basically the matrix that's surrounding the muscle and hooking the muscle to the tendon was regulating everything about development of the diaphragm's muscle. It controlled normal development, and that actually mutations in the connective tissue were the cause of this very common birth defect.
At first it was it's just a really interesting scientific questions and then over the years as we started to make progress and we realized that actually maybe we could gain some serious insights, then I was very interested in connecting with the families. In part just because you get interested in it and you want to know really what is the situation if you have CDH. And then in part because it turns out the family members have lots of information that they don't realize that they have that gives you incredible insight into the birth defect.
Interviewer: Is it fair to say that this intersection with this disease has totally refocused, at least part of your lab?
Dr. Kardon: Yes. I had always worked on limb development and limb defects, but now more than half the lab is working on the diaphragm.
Interviewer: You have mentioned that they have information that has helped you. What kind of information?
Dr. Kardon: So for instance, I was talking to parents in D.C. and there were at least two parents who were talking about CDH babies in which also in that baby was not only this diaphragmatic hernia, but they had a cleft palate. And it turns out that there are developmental processes that are very strongly linked between the two and so to see them repeatedly in the same patient gives you some insight into the science behind it, so that was something that was really interesting.
Interviewer: Do you think that you've been able to give something back to them? Do you talk to them about your science and do they understand it?
Dr. Kardon: Right. Actually, I think there's one way that was sort of surprising that I think maybe had the most impact on them. There's an enormous variability in the single diagnosis and for the families that's really hard. So it is really hard to be the parent of a child who dies and meet up and see a parent of a kid who also has the same defect, but looks completely normal. And I think that's very difficult, I think it's difficult to be a cohesive group when there's such different outcomes.
So I think the thing that I could contribute to that conversation is to tell them that there are good genetic reasons as to why there's such variability and in fact this is one of the real scientific conundrums about the defect is that there are many ways to get a hernia. And in part some of those ways to get it involves this de novo mutations that arise in the kids and when and where those mutations arise really affects the outcome. And so that when as a parent, as a pregnant mother, you're diagnosed at 20 weeks with the CDH, you have absolutely no idea what's going to happen when your baby is born.
Interviewer: So it's not their fault.
Dr. Kardon: It's not their fault and it's very different from let's say, people who have Duchenne muscular dystrophy, where they're all pretty... there's some uniformity to the disease. There's a pretty general progression. There is not any uniformity in CDH, which makes it really difficult.
Interviewer: Do you think they take comfort? Some people have taken comfort in knowing that?
Dr. Kardon: I don't know, it's hard to know. This is my first sort of serious interaction with patients... sorry, with parents of patients and with patients, and some of the parents it was pretty raw. There were parents who were at this meeting who have lost their baby only a month ago. So they're in a tough place.
Interviewer: Yeah. Obviously this turned into kind of an emotional investment, as well as a time investment. I don't know, what does that mean for you?
Dr. Kardon: I don't know. I make a pretty serious commitment to do the science, and that commitment means that I'm taking time away from my family, and so I would hope that what I'm doing should be something that's important and makes an impact on someone. And so it's helpful to see who that would make a difference to. And I really am still a basic scientist. But it's kind of hard when you're working in this direction and you can see that there are hints that you may be able to do something in terms of therapy and it feels like it's a challenge, it's kind of this puzzle, "Why wouldn't you do it?" We could actually do some clinical trials using mice, now wouldn't that be really interesting?
Interviewer: Is there anything that you can think of that you want to make sure to get across?
Dr. Kardon: I guess the one thing it's really that scientists sometimes shy away from interacting with the patients of the families and it seems a shame, it seems like you can learn so much from them. They have an enormous amount of knowledge that they don't even realize that they have about the disease. It's just buried in them, funny little observations that they have made. And you come in there with a completely different set of eyes and talk to them, and they'll say something and you'll go, "Wait, wait, say that again. What is it? What happened here?" And you learn a huge amount from them, so I think it's really worth while.
Announcer: Interesting, informative, and all in the name of better health. This is the Scope Health Science's Radio.
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Congenital diaphragmatic hernia (CDH) is not as…
Date Recorded
March 27, 2015 Science Topics
Health Sciences Transcription
Interviewer: Research that gives us a new understanding of common yet relatively unknown birth defect, congenital diaphragmatic hernia.
Examining the latest research and telling you about the latest breakthroughs, The Science and Research show is on The Scope.
I'm talking with Dr. Gabrielle Kardon, Associate Professor in Human Genetics at the University of Utah. She's just published research in the journal Nature Genetics that gives us a new perspective into the causes of congenital diaphragmatic hernia or CDH. Dr. Kardon, I had not heard of CDH before can explain what that is?
Dr. Kardon: Most people are familiar with hernias as inguinal hernias and so in an inguinal hernia, you have a weakness in your abdominal wall and your guts basically protrude through your abdomen. And what you can think of CDH as an inguinal hernia in reverse. So instead of your guts going downwards they go upwards through to weakened diaphragm and up into the thoracic cavity and the big problem is if you have your liver and your guts into thoracic cavity, they will basically interfere with the growth of the lungs.
Interviewer: Before your research what did we know about how this birth defect happens?
Dr. Kardon: So I would say the majority of the information about CDH actually comes from human geneticist. They take blood samples from CDH patients and they look at the genetics and they look and see whether there are mutations in their genes or the regions of their chromosomes that are deleted. And so basically what we know is a whole lot of genes and quite a few chromosomal regions that are strongly correlated with the incidents of CDH. And the real problem has been that we have no idea how these mutations lead to CDH. And I think that's the problem that we were interested in addressing. How do we go from a mutation to developing a weakness in the diaphragm?
Interviewer: And that's part of why your research is so insightful because you came at it from a totally different approach than what's been done before?
Dr. Kardon: Right. So we just started by looking at how the diaphragm normally form and basically we looked at a lot of different kinds of mice where we could genetically label different components of the developing embryo to track where did the muscle cells come from, where does the connective tissue come from, where does the tendon come from and how they get linked up.
Interviewer: And that's part of your research too is understanding what happens normally and then understanding what happens in the context of CDH.
Dr. Kardon: Right.
Interviewer: So what do we know now about what happens normally and then what goes wrong?
Dr. Kardon: Basically the diaphragm you can think of as a ring of muscle cells and that inside the center of that ring the muscle cells are hooked up to tendons and surrounding each one of those muscle cells is a bunch of connective tissues or collagen. And that collagen is linking the muscle to the tendon and also the muscle to the bone.
And so normally we think of the connective tissue as basically providing structural support and holding the thing together, but basically playing a pretty passive role. And then the surprising thing that we found in development is that the connective tissue was the driving force for diaphragm development. It basically told all the other cells what to do.
And so we basically took our cue from the human genetics studies and we looked at basically one of the most prominent genes that has been identified as playing a role in CDH and this was a gene that's called GATA4. And what we used was some fancy tricks so we could knock out GATA4 and its function in particular cells.
And what we found that was really surprising is that GATA4 was essential in the connective tissue. Now when you got rid of GATA4 in the connective tissue you always got hernias and the hernias looked just like the patient hernias. And so we had weaknesses in the diaphragm. We had the liver herniating through the diaphragm and the mice had small lungs and just like the human patients most of those mice died at birth.
Interviewer: One thing that was amazing to me is that you got these hernias every time you did that experiment, which doesn't happen very often in science.
Dr. Kardon: Right. We have now looked at hundreds of these mice and every single time we knock out the gene in the connective tissue and I should point out not in the muscle. So in the connective tissue we have these hernias.
Interviewer: The way these hernias develop is actually little bit counterintuitive.
Dr. Kardon: Right, so there's just decades of data on hernias in patients and from that data, doctors had always suggested that hernias were holes in the diaphragm and that through these holes, the liver and the guts can herniate through. And what we found is that in the mice, where we can observe the formation of hernias from the very beginning, what we found is that there hernias are not initially holes in fact what they are, are regions of connective tissue but that have no muscle in them. And so they are not actually holes.
So the holes may form later as the liver keeps protruding through this region which is really weak and has no muscle but initially it doesn't start out as a hole. So that's completely counter with the dogma that is from the physicians and pediatric surgeons.
Interviewer: Now that you have all this basic information what can you do with that?
Dr. Kardon: So we know that the connective tissue is the problem and the other thing that was really surprisingly learned is that the defect is really early. So typically in humans a mother learns that her baby has CDH by an ultrasound at roughly 20 weeks. And this is quite late and in the mice, where they have a much shorter gestation time, we see herniation about two thirds of the way through gestation but when we look earlier we see that the defect is much, much, much earlier. In fact the defect would correspond to roughly between 40 and 60 days in utero in a human so it's much earlier.
But the idea is that we could actually go and test some potential therapies in our mouse embryos and see if we could rescue these mice, that we know will get hernias if we allow them to develop. And can we somehow intervene? So obviously clinical trials is a big deal and especially when you're talking about doing something potentially in utero. So you need to be able to try to test things in something other than a human. And the trick has been that we've never had basically a very good mouse model of CDH and so I think it's an excellent starting point that we haven't had before.
Interviewer: Interesting, informative, and all in the name of better health. This is The Scope Health Sciences Radio.
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