Dr. Mike Smith (Host): Welcome to Pediatrics in Practice, a CME podcast. I'm Dr. Mike. And with me is Dr. Scott Younger from Children's Mercy. He's the Director of Disease Gene Engineering. Today, we're diving into the fascinating world of genomic medicine and pediatrics, what pediatricians need to know now. Dr. Younger, welcome to the show.

Let's go ahead and start off with how do you define genomic medicine and pediatrics. And why is it becoming increasingly relevant for general pediatricians to know not just specialists like yourself?

Dr. Scott Younger: Well, first of all, thank you for having me on the podcast. I'm excited to chat today. And to get to your question, so genomic medicine is basically just the process of leveraging genetic or genomic information to achieve tasks like facilitating disease diagnosis ranging all the way to guiding treatment plans for patients, right?

So, I think about this as kind of maybe like a car. If your car won't start, like, 50 years ago, you might take it to the neighborhood mechanic and hopefully work through a process and find the problem. Today, through technological advances, we have new tools we can use. We have these diagnostic boxes we can plug in. And you get a code, and maybe sometimes that code says the battery cable's loose. And that doesn't solve the problem, but it tells you what you need to do. Sometimes that code might say there's a problem with the fuel system. Now that's more broad and there's more to look into, but at least it gives you some direction, as to where you should be looking. So, that's kind of how I think about genomic medicine and the role that it plays today in pediatrics.

Host: I like that. That's a good analogy. But from your perspective, where is genomics already influencing pediatric care like today? Like, how is it being used right now?

Dr. Scott Younger: I can give, you know, two examples of things that we've accomplished in our lab. One of them was an example of a patient who we identified, the underlying genetic cause of disease for specifically a Duchenne muscular dystrophy. And that underlying genetic cause was amenable to treatment with type of molecule called an antisense oligonucleotide. So in the lab, we actually did a preclinical development of what would be an individualized therapeutic that could one day be used to treat just that one specific patient. Again, that was all guided through the genetic diagnosis.

And then, another case that was really amazing, what we were able to achieve in lab, is through a genetic diagnosis identifying the underlying cause of disease for a patient with intractable epilepsy, which ended up being a faulty calcium channel. We were able to search for existing drugs that targeted that calcium channel. And what we were able to do was do an individualized drug repurposing. So, finding an available drug that we could use off-label. And that was actually successfully used to resolve seizures in the patient. So again, that genetic diagnosis actually guided the treatment in ways that we would not have been able to identify without that.

Host: Well, let's expand on that a little bit. So, what are some of the common clinical scenarios where a pediatrician should consider, you know, whether genomics might help provide answers for a patient or a family?

Dr. Scott Younger: I think you have kind of two things on different ends of the spectrum. One is where you, have, you know, an array of clinical presentations with very unclear etiology. That's an example where you might want to dig into the genetics and see if there's something there that could explain these things.

And then, on the other end of the spectrum are scenarios where you have maybe a clinical presentation that's a little more common, but really just could be caused by a wide variety of underlying issues. And again, like back to that car diagnostics analogy, just giving you the information of where should I be looking or where is the best first place to start looking for what's causing these conditions.

Host: You know, Dr. Younger, when I was in medical school, I had a genomic engineer once tell me—now, this is a long time ago, right? This is now in your early '90s. He had said that someday I'm going to have a book that I can just open, pick the disease, pick the abnormal gene, abnormal protein, and then have an answer of what to treat with. And that was so impressive to me. That was like, "Oh, that's what genes and genomics is going to do for us." Is that reasonable? Is that how someone like a general practitioner can think about this?

Dr. Scott Younger: That's an aspirational goal for sure. That is not the way it is now or it will likely be in our lifetimes because the amount of information you have to collect to truly understand these things. So, it's important to note because there's not a situation—or very few situations, I should say—that a clinical diagnosis or a genetic diagnosis, is going to give you a crystal-clear path forward. Particularly, we work a lot in rare disease. These diseases are complex, right? So, they give us tools and information. But it still requires really great pediatricians and specialists to understand the patients and how to leverage that information to treat them as individuals in the best way.

Host: I think the genomic engineer that told us that was being a little, you know, sarcastic. But anyways, when you think about where we're at with genomic medicine, and you think about some of the conditions that, you know, you've highlighted already what's your hope for this? Like, what do you see in the near future, far future for genomic medicine? I mean, how far are we going to be able to go?

Dr. Scott Younger: So, that's a really great question. And the answer, I think, lies less in the technology itself and more in the ways that we implement and execute the tools and democratize access. So, we've shown that we can, you know, achieve great success in certain cases. But in a lot of cases, this technology is not reaching the people that would need it most.

So, the ways that we implement genomic medicine and the healthcare system, unless it is kind of boutique tools, I think that's really the path forward. And the major challenge that lies ahead, there's still technology that needs to be advanced and grown and developed. But we can't set aside the fact that we've got to figure out how to get this technology to the people that need it.

Host: Yeah. It seems—and I'd like to get your opinion on this—it does seem that understanding genomic medicine a little bit more than, you know, just genetics in general, that we have a greater appreciation for personalized, not just personalized medicine and personalized treatment, but personalized disease that a prostate cancer in me is not the same as you genetically speaking. Is that true? Is that something that you would agree with?

Dr. Scott Younger: That's absolutely true. And that's why we've talked a lot about genetic medicine or genomic medicine. Another area that we're advancing in my lab is working in what we call individualized cellular models where we're able to actually take cells from a patient and develop advanced cell models in a dish. And that allows us to ask questions and do experiments to inform us about individual's condition because, again, sequencing a genome doesn't tell us everything and we don't fully understand the genome quite yet. So even with the sequence information, there's still things we're just not going to be able to understand. So, each individual is unique, and a disease will present uniquely in each person and that does need to be appreciated.

Host: Maybe if the genomic engineer that told me about that book, maybe today he might say that each person's going to have a book. And you open up that book for Scott Younger and if he has this issue, This is your treatment. Maybe it's going to be more like that.

Dr. Scott Younger: Yeah. Again, an aspirational goal for sure. But yeah, that would be the idea that we would strive for.

Host: Now, what happens when genomic testing doesn't lead to a targeted therapy or a better therapy, how can having that diagnosis, that genetic diagnosis, change care or support for a patient and the families?

Dr. Scott Younger: It's important for us to appreciate that the going rate for achieving a diagnosis from whole genome sequencing, for example, sits at around 40%. So, that helps a lot of people, but it's by no means a one-stop shop for getting your diagnosis.

But what it does is it can help you rule things out. It can also potentially help you identify their communities with similar presentations and get that kind of community, and understanding, that can kind of help on the personal level, even if you can't get that underlying genetic cause.

Host: You know, when it comes to genes themselves, I'm going to back way up for a moment, and, you know, when you're talking to the patient, the parents, what have you, how do you explain all this? I think most people know just with basic, even middle school science, that we all have genes, DNA. Half come from mom, half come from dad. And we all, as humans, we share these genes in a sense. How do you explain then genetic testing? And what you're actually measuring and looking for?

Dr. Scott Younger: So, each gene encodes a protein. The protein's kind of the working unit. And so, what you're doing with the genome sequencing, for example, we're looking across those working units that we know of. We know what they do and their general processes they're involved in. And that allows us to identify where pathways and processes aren't working right inside of a cell.

I mentioned a calcium channel. So, calcium flux plays a role in muscle contraction. It can play a role in neuronal firing. So, that kind of tells us the underlying molecular cause and kind of attribute those clinical presentations back to the underlying genetics. So, it kind of just provides that blueprint. I guess for the analogy, it's the Chilton guide, I don't know if they still print those or not.

Uh,

Host: I don 't know. I don't think so.

Dr. Scott Younger: They they live online somewhere. Yes.

Host: No, that's good. I think that's helpful for pediatricians. Because, you know, here's what's happening, Dr. Younger, it's not just the genomic engineers like yourself with PhDs that are having these conversations anymore. General practitioners are having these conversations. Patients are interested in gene therapies and genetic diagnosis because they see it all over social channels and stuff. And so, this is, I think, an important question. What do pediatricians really need to understand versus what should be handled by someone like you?

Dr. Scott Younger: I was thinking about this this morning. Like, I think there is a difference between biology, and physiology, and sometimes thinking those two things always go kind of hand in hand. Maybe we need to take a step back. So, understanding gene therapy, how it works, the implications, and the underlying technology of that is somewhat separate than the actual physiology of disease. And so, you do need somebody that understands the nuts and bolts. Especially with genetic therapy or gene therapies, these aren't your maybe typical small molecule drug that you might take or prescribe a little more, or a little more available, a little more freely.

So, I think you do need somebody with necessary expertise, at least around to teach pediatricians kind of the language that should be used and when those questions should be guided to somebody with more expertise with that knowledge.

Host: So as you study all this in research, the latest developments, innovations in genomics, what do you think are the most important ones for pediatricians to be aware of? And how do you see the general practitioner, the general pediatrician, how do you see their role evolving in all this as your field growth?

Dr. Scott Younger: So, that comes back to an answer I gave you earlier, which really is democratized access to the technology and the way that understanding or charting the path forward about how that enters into kind of more general practice. I've given you examples of how we can use that information to guide treatments.

Now, a lot of times we see in what we do is people kind of do the proof of concept where they show something can be done. But really, that path to getting there isn't the same path that's going to lead to widespread adoption, or implementation on a large scale. So, that's a different problem. And so, not every patient or every clinician is going to be able to build up this giant work product to show something that is a proof of concept. We need to understand where this can be implemented. For example, how can we standardize or make standard of care to deploy genomic medicine, for example, whole genome sequencing, and a pipeline that allows the clinician to have access to that information without having to do all the work themselves.

And I think that's really the path forward and clinicians, pediatricians are obviously going to be required to play a role in that, because we understand how the technology works, but we don't fully understand the best path forward for getting it widely adopted.

Host: That's fascinating. You're listening to Dr. Scott Younger from Children's Mercy. He's the Director of Disease Gene Engineering. Any last words for the listening audience about genomic medicine?

Dr. Scott Younger: I just appreciate the opportunity to chat about this. i do think we should be thinking more broadly about how we can implement the tools and technologies at scale, making these more standard of care, and kind of the barriers that are there, and what we need to work on, just as a broad field in pediatrics.

Host: Dr. Younger, thank you so much for coming on. I have so many more questions for you. So, you're going to have to come on back and talk more about this fascinating field. For more information, you can go to cmkc.link/cmepodcast. If you enjoyed this podcast, please share it and explore our entire podcast library for topics that interest you. This is Pediatrics in Practice. I'm Dr. Mike. Thanks for listening.