Karie Dozer: [00:00:05] I'm Karie Dozer, and this is TGen Talks. Much of the research at TGen centers on specific diseases. Scientists here are creating personalized genomic treatments for specific types of cancers, neurological disorders and pathogens. But a special part of the research is for kids only. Research at the Center for a Rare Childhood Disorders tries to find treatments. Sure. But first, it sometimes has to find a disorder. Some of TGen's youngest patients don't even have a diagnosis because what they suffer from might be so rare that it doesn't even have a name. I sat down with one of the leaders at the center, often called C4RCD for Short, to find out how this detective work is going and what it means for parents to finally find a cause for the symptoms their children have dealt with their entire lives. And I'm here at TGen with Keri Ramsey. Keri, thanks for joining me on TGen Talks today. Tell me your title with the Center for Rare Childhood Disorders and with TGen overall. [00:01:06][60.4]
Keri Ramsey: [00:01:06] Yeah, I'm the clinical co-director of the center and I do a lot of clinical research coordinating enrolling patients in our research studies, helping to give back results and help run one of our pharmaceutical clinical trials. [00:01:21][14.4]
Karie Dozer: [00:01:22] For people who don't know a lot about the center. What is it, in a nutshell? [00:01:24][2.6]
Keri Ramsey: [00:01:25] I think it's like a little gem in the desert out here in Arizona. We really focus on individuals that have rare disease. We've also have a couple pharmaceutical clinical trials where we're actually using drugs that are, you know, under review to see if we can help improve the quality of life in patients. [00:01:47][21.8]
Karie Dozer: [00:01:48] So who generally finds you? The parents of a child who have something that that hasn't been diagnosed in their child? [00:01:53][5.5]
Keri Ramsey: [00:01:54] You know? Yeah, I mean, parents are amazing. They are, you know, they get online and they do these amazing searches and they can come across us that way, sometimes through, you know, Facebook groups, families will refer other families to us. And then we also have really great collaboration with local physicians and doctors and doctors all across the country who refer their patients. [00:02:17][22.4]
Karie Dozer: [00:02:17] You come face to face with actual people more than more than a lot of researchers do at TGen. [00:02:22][5.0]
Keri Ramsey: [00:02:23] Yeah, I think that's one of the reasons why I ended up taking this role. I originally started at the bench doing lab research, and I really just had this strong desire to interact with patients. And that's really what is what makes my day is having families come into the clinic and interacting with their kids and just that that whole process brings so much joy to my life. [00:02:46][23.0]
Karie Dozer: [00:02:46] Patients who come to the Center for Childhood Disorders and their parents say that it helps them to give a name or a label or even a category to something that's been afflicting their child. But after the the child has a diagnosis, do you then help direct treatment or coordinate treatment? How do you then make that child's life better now that we have something to fill in the blank? [00:03:09][22.8]
Keri Ramsey: [00:03:10] Sure. Yeah, I mean, that's a great question. You know, it can be complicated. There is over 7,000 rare disorders. So, you know, at TGen we can't possibly study all of them. But typically what we do is we try to find experts in the field who are studying that disease. Sometimes we are the center. You know, we do some studies into tubular sclerosis, rhett syndrome, mitochondrial disease, and then that's definitely a situation where we can bring the research in-house and, you know, study the patients like cell lines or creating animal models like here at TGen. [00:03:41][31.8]
Karie Dozer: [00:03:42] How often does a patient come to you with no diagnosis and eventually get one? [00:03:47][4.4]
Keri Ramsey: [00:03:47] You know, we we have about a 40 percent diagnostic rate right now, which is about the national average, even though this type of testing is incredibly comprehensive and detailed. You know, there are still a lot of families out there that aren't finding answers. And so we've actually collaborated with a company called Illumina. They are. They're one of the companies that helped create the technology that we use for sequencing these individuals. And in this collaboration, we're going back and we're looking at over 200 of our unsolved families. So these are families that have had what we call whole exome sequencing done at TGen and without a genetic diagnosis. [00:04:28][40.4]
Karie Dozer: [00:04:29] OK, what's an exome? [00:04:29][0.5]
Keri Ramsey: [00:04:30] That's a great question. So our DNA, you know, is an almost every cell in our body. It's made up of these chemicals called nucleotides, and there are over 20,000 genes in that DNA that make proteins that decide what you know it's going to, that they're the workers in our body. And so with exome sequencing, we're specifically looking at the part of the genome that where the genes code for proteins, so the genes are made into protein. So it turns out that's actually only like two percent of our whole genome and 98 percent of it is actually this part of the DNA that we don't know a lot about. We don't really know when its function is in the cell. It gets cut out of the DNA before protein is made. So with these 200 families that were going back and we're doing a more comprehensive type of sequencing. [00:05:20][49.7]
Karie Dozer: [00:05:21] People who don't have answers who say, can you? [00:05:23][1.7]
Keri Ramsey: [00:05:23] Yeah. So, you know, we've looked at your two percent of the genome like the most important part of your genome. But now we're going to look at everything else. So the entire absolutely entire genome, which just blows my mind because when the first person was sequenced, you know, in 2003, you know, it took over 10 years and $3 billion. And we're doing this same type of technology with these families right now like it. [00:05:45][22.1]
Karie Dozer: [00:05:46] Like not not instantaneously, but pretty quickly. [00:05:48][2.3]
Keri Ramsey: [00:05:48] Yeah, yeah, definitely. And we are we're also looking at something called RNA. We're doing RNA sequencing. We're really trying. To approach these families from multiple directions. I think that this has been part of a big effort, you know, across across the world really is to help these families where we just aren't fighting a diagnosis like what is really the cause, what's going on? [00:06:09][20.9]
Karie Dozer: [00:06:10] You're doing so-called cold cases. You're looking at cases where you didn't get the answer that you were looking for. How do you choose those cold cases to go back in to? In other words, is there a likelihood that that makes you choose these cases to look into again? [00:06:25][15.2]
Keri Ramsey: [00:06:26] So we've we've really been sequencing these families since 2012, so almost 10 years. The technology was very different back then. It's gotten so much better. And our methods of analyzing the data and even our understanding of the human genome has has just made like leaps and bounds in the last 10 years. So we're really starting to go back from those original families and kind of working our way up. And, you know, I'm really proud to say of the families that we have sequenced so far in this project. We've had a 10 percent diagnostic rate. So these are families that didn't have an answer. And now they do. [00:06:59][33.1]
Karie Dozer: [00:07:00] When you talk about a 40 percent success rate and you compared it, you said that's about standard. Yeah. Number one, you're talking about other places like TGen that are doing this similarly. You're using similar technology and you're also talking about cases that have been looked at maybe hundreds of times by different specialists. Yeah. So it's 40 percent doesn't sound like a huge number, but it really is considering the number of times that these cases have have bent have gotten a zero diagnosis. [00:07:27][27.7]
Keri Ramsey: [00:07:28] Yeah, exactly. And I mean, when you tell these families 40 percent, they don't look at it as a small number and they look at it as hope. You know that this is an amazing opportunity for their families and it could provide an answer. [00:07:37][9.3]
Karie Dozer: [00:07:38] So what are some of the success stories? What have you found with this, with this technology that obviously didn't know what you were looking for, but like what's an example of a cold case that you guys recently cracked, so to speak? [00:07:50][12.1]
Keri Ramsey: [00:07:50] Yeah. You know, so we had a family where we, you know, we originally thought we had the diagnosis. This was like, you know, again seven years ago. And then it turns out that, you know, at the time there was this, there were only like a thousand controls or unaffected individuals that had been sequenced. So we really didn't have a good idea of the frequency of these changes in the DNA or these mutations. So a few years later, we figured out that, oh no, this isn't their diagnosis. These changes that we thought are actually pretty common. And so, you know, they went from having a diagnosis to not having a diagnosis, which is bad news. Blows my mind. And then through this program, through this collaboration, we we really have found the answer for them. It turns out the the changes that they have in their DNA have been seen in other individuals. There's no question that this is the diagnosis. And the amazing thing too, is that this disorder wasn't really describe until January of 2021. So even though we sequence them, you know, six or seven years ago, we wouldn't have made this diagnosis because this disorder just wasn't even, you know, wasn't even a disorder. [00:09:00][69.7]
Karie Dozer: [00:09:01] So people listening might wonder if there are others affected with it, why it wasn't diagnosed, but just because you and I suffer from the same disorder doesn't mean we have the same symptoms, right? [00:09:12][10.6]
Keri Ramsey: [00:09:12] Sure. I mean, take epilepsy. That's a great example. You know, there are probably, you know, close to several hundred genes where you can have mutations and they'll cause seizures. So, you know, no two patients are necessarily alike. [00:09:26][13.8]
Karie Dozer: [00:09:27] So when you go back to a family and you say, we have good news, we have a better diagnosis, we have a different diagnosis. Yeah, what is the family's reaction in general? Are they are they pleased or are they upset that maybe they didn't get the right diagnosis the first time? [00:09:42][14.7]
Keri Ramsey: [00:09:43] You know, that's a great question, and I think so many people would react in so many different ways, I think. I think the fact that there are other children out there, other individuals that have the same mutation, and we feel very confident about these results. And it turns out for this specific disorder, the one of the people who originally described this disorder in the literature is one of our collaborators in Pittsburgh. So, you know, we're we're connecting the family with those researchers and there's a lot of interest in the specific disorder. So I think, you know, even though we're like, Oh, now we've come with you with another diagnosis, at least we have some tools and some resources and and there's a Facebook page that has over 100 individuals, so there might be a little bit more support for them this time. [00:10:26][43.3]
Karie Dozer: [00:10:27] There's not just a diagnosis, there's a community for them. [00:10:29][2.3]
Keri Ramsey: [00:10:29] Community. Exactly. [00:10:30][0.5]
Karie Dozer: [00:10:30] So what's next in terms of rare childhood disorders? Do you ever hope to be able to say you can diagnose everything? [00:10:37][7.1]
Keri Ramsey: [00:10:39] I mean, I would love that. I unfortunately, I think genetics is just so complicated, so much more complicated. Like we're getting the low hanging fruit here. You know, we're finding, you know, mutations in disorders where it's just one gene. But for some of these families, it may be that they have changes in multiple genes, and it's just going to be a little bit harder for us to figure that out. They may also not have mutations in the DNA. There may be something going on at a different level. So I think what's amazing about TGen is we're always going to be exposed to new technology and different ways to look at the genome and to do noninvasive testing through the blood or saliva. And so I think as this new technology comes out, it's going to our center is always going to be like a number one priority. Oh, let's test it out and these kids and see if this will improve our diagnostic rate. [00:11:25][46.5]
Karie Dozer: [00:11:26] When you diagnose something new that nobody's seen before or given a name. What about the science that goes into the the book of knowledge on that disorder? How do you collaborate with other researchers and to try to build that book so the next person has something to look to? [00:11:41][15.1]
Keri Ramsey: [00:11:41] Yeah, I mean, I think a great example of that is our research in Okur-Chung Neurodevelopmental syndrome. So that's a disorder that really until a few years ago wasn't even known. And then one of the families that is in our study started the foundation in a support group. And I mean, she's this mom is just amazing what she's done really in creating, you know, yearly family meetings, creating a medical advisory board. It's unbelievable. And I think, you know, we've been a part of that process along the way and in helping recruit other scientists to study this disorder. So, you know, I think for a lot of families, they're like, OK, we have a diagnosis now. Now I want to find a treatment for my child now. But you say, Gosh, well, this disorder was just discovered in January this year, like we didn't even know about it. There's no treatment yet, you know? But I think, you know, a lot of people talk about gene therapy and gene editing. You know, it's being used in a couple of different disorders right now has been approved by the FDA. And I think this is really where the the treatment and therapy options are going to be in in the near future and especially with genetic disorders. If you can find a diagnosis for your child, then then there may be hope that this type of therapy could be applied in the future. [00:13:04][82.8]
Karie Dozer: [00:13:05] Is there a category that occurs in children? Predominantly? Do you see one type of disorder more? [00:13:11][6.2]
Keri Ramsey: [00:13:12] Well, I mean, our medical director is a pediatric neurologist, so we do see a lot of patients with a neurological component. I think, you know, autism is a perfect example where I wouldn't say that that's a rare disorder, right? And certainly not rare anymore. Yeah, but it has a lot of neurological components. And so we do see, you know, patients with autism, but other factors. I think there is a lot of understanding of genetics in neurological disease, different types of kidney disease, different types of skin disorders, muscle muscular disease. But some of the other fields there just haven't been as much research or a lot known. So I think we definitely see a lot of neurological patients. [00:13:57][45.1]
Karie Dozer: [00:13:58] I'm going to ask you to speculate a little bit, but knowing how much more we know now than we did 10 years ago, 20 years ago, 50 years ago, how much do you think we still don't know? [00:14:08][10.6]
Keri Ramsey: [00:14:08] I think that's an incredibly hard question to answer, but I always look at the sci fi movies and TV shows, and I think it's amazing. You know what- what kind of what people envision that the human race will be able to do. So, you know, we envision that we're going to be able to treat cancer, treat these disorders. And I think that there is a lot of progress and I think just even having sequenced the DNA has made a huge difference. You know, the human genome in general in terms of identifying mutations and telling whether persons at risk for disease. And we're just going to keep chugging along. I don't know. I don't know when we're going to, like, solve it all, [00:14:49][40.2]
Karie Dozer: [00:14:49] but not in our lifetimes. Now, finally, if someone listening has never heard of the Center for Rare Childhood Disorders, what would you tell them about it? What would be your elevator speech, so to speak? [00:15:00][11.1]
Keri Ramsey: [00:15:02] I think if you have a child with a rare disease, it can be very difficult to navigate. You see lots of specialists. You're on, maybe you're on lots of Facebook pages, you're communicating with a lot of families. And I think where we kind of come in is to help families that feel like they're overwhelmed. They haven't had help with an answer. Maybe they've had testing before and it's just a negative and they want another look, someone else to help. I would say, you know, if you have a family that qualifies for one of our research studies or clinical trials where we're able to see your patient here in Arizona so that you don't have to travel across the country, you know, we really help a lot of the local families here as you know. [00:15:50][48.5]
Karie Dozer: [00:15:51] You've probably met a lot of parents who've traveled a lot of miles to get answers. [00:15:54][3.0]
Keri Ramsey: [00:15:55] Yeah, yeah. I mean, I guess I would just say the other thing that I think is really special about the center is that the patients that we see, you know, they don't pay any money to get tested here. We, you know, we we have money that's raised through philanthropy. The TGen Foundation is amazing in raising funds for our center. We receive grants from the National Institute of Health and other organizations around the country. But I think for a lot of these families, you know, they don't have the funds to to be able to to participate in this kind of research or this sort of genetic sequencing. [00:16:33][38.1]
Karie Dozer: [00:16:34] So because caring for their kids has been expensive enough. Yeah, exactly. Awesome. Well, it must be rewarding work. Thanks for taking the time to talk about it. [00:16:41][6.8]
Keri Ramsey: [00:16:41] Thank you, Karie. [00:16:41][0.4]
Karie Dozer: [00:16:44] TGen conducts numerous clinical trials in the field of rare childhood disorders. To learn more about the center, take a virtual tour and find out if a child, you know, might be eligible. Go to TGen.org/center. TGen is an Arizona based nonprofit medical research institute dedicated to conducting groundbreaking research with life-changing results. TGen is an affiliate of City of Hope. You can find more of these podcasts at TGen.org/TGenTalks, or on Apple Podcasts. We're TGen Talks. I'm Keri Dozier. [00:16:44][0.0]
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