Pediatric precision health: Beyond the diagnostic odyssey

00:00:00 Music 00:00:03 Host: Hello and welcome to this edition of Cook Children's Dog Talk. It's a very busy day here in the Child Life Zone at Cook Children's, so you may hear a little background noise. It is really exciting to be able to introduce our guest for this episode of Doc Talk, Dennis Lal, PhD. Dr. Lal is an executive scientist in the Pediatric Precision Health program at Cook Children's Health Care System. In addition to his role at Cook Children's, Dr. Lal is a professor and executive director of the Center of Innovation in Health Informatics, Healthcare Scale Informatics, Precision Health, and Clinical AI Initiatives. He is also an internationally recognized genomic scientist and leader in health informatics. A self-described unconventional researcher, Dr. Lal's approach focuses on creative and innovative approaches to today's increasingly data-driven research challenges, with the goal of turning those challenges into successes that make a direct impact on patients' lives to end what is often called the diagnostic odyssey, when families spend years trying to receive an accurate genetic diagnosis. Throughout his career, he has contributed to large-scale genomics research consortia and has served as a scientific advisor to several foundations supporting families affected by rare genetic epilepsies. His multidisciplinary research program integrates technological, computational, and data-driven approaches to improve understanding of epilepsy and related neurodevelopmental disorders. All of which will bring a new era of care for kids with rare diseases, their families, and physicians who care for them. It's a great pleasure to welcome you, Dr. Lal. 00:01:48 Dennis Lal: Thank you so much. I'm glad to be here. 00:01:57 Host: In 400 BC, Hippocrates put forth the idea that patients were more important than the disease, setting the wheels in motion toward precision medicine. Now, 2,400 years later, I'm sure he'd be really pleased to know that we've arrived not only at precision medicine but also precision health, and more specifically, the Center of Pediatric Precision Health here at Cook Children's. Can you take us through what precision health is, why this is important, and why now? 00:02:29 Dennis Lal: I can talk probably very long about that question. So on the one hand, we are living in an incredible time that we have precision diagnostics. Many of our diseases have a biological reason. Often we just say genetics, which we didn't know until recently. So, and with recently, I mean, really, we have identified for more than 7,000 rare diseases the genetic cause only in the last 10, 15, years. And for many more, we are just discovering every week the genetic reason. And these are particularly very severe diseases, which we have at Cook Children's quite a bit. We estimate that's around about one in five children who are in the hospital, and particularly if they are longer in the hospital, have a rare disease where genetics plays a role or is for certain the cause. And up till let's say 10, 15 years ago, there was no way how we could diagnose them technology-wise. And only 10, 15 years ago we started to be able to diagnose, let's say, 50 to 100 of such disorders. And today we have technology where we can diagnose them all in a single test. And since two years, the Texas Medicaid is paying for it. Medicaid is used often as a marker if many insurances will pay for it. So it's very recent that we have this technology in hand to really diagnose children. Where, in all human history, people would always wonder, "Why is this child sick?" And no other imaging, no other assessment, no other blood test could tell the family or the child why the individual is sick, why is always in the hospital, and this is now a completely new area in medical history, and this is the diagnostic part. But separately, if you follow the news, you will learn that there's technologies like CRISPR, so where we can change back DNA segments which are mutated to the correct DNA letters, and there's also gene therapies which are a completely different game today compared to 20 years ago when they were first announced, and a lot of other very innovative technology involvements or new products. And these are now the first, let's say 10-50, of them have been now approved, and they're typically for ultra rare diseases. But there's more common diseases also coming now, and there's a couple examples. And the recent years are there now. And if you look at the clinical trial landscape, there is an explosion of new therapies, particularly in the biotech area, with these new gene editing and gene therapy techniques, which are now there to treat all those rare diseases. And this is not surprising because if you can correct a letter in one gene, you basically can correct a letter in all genes. And so the execution of the clinical trial is what is the holdup at the moment because these technologies there are very generic, and so the medicine is about to change from the therapeutic part, particularly for diseases where there was no solution ever, which make up most of the health care utilization in our system in the hospital setting, and at the same time we can diagnose all children. So, to come back to your original question, what is precision health? It's really enabling us as a health care system to make use of these new opportunities, and this will require optimizing the systems which enable the delivery of such diagnostics of the decision support for providers, or providing them with enough resources, and at the same time also enhancing the knowledge base from every one of our clinical partners, because a lot of these technologies only available in the last, literally, two to three years, where basically almost all of the providers have not been taught in school because this is not school knowledge. I have trained a lot of medical doctors and residents in the recent years, also medical students, and this is not really in the curriculum even. So that's what we are trying to tackle in the center. So we're doing also a lot of research, but in general, trying to shape Cook Children's around the new technologies which are now available that we can serve every child with these new innovations. 00:06:45 Host: You've described the precision care workforce as a concerted effort across research, health care, IT leadership, compliance, legal, etc. Take us through the structure and how it differs from today's workforce. 00:06:59 Dennis Lal: This area is so new that there's no game plan. And at the very first, we wanted to help children. And when we want to help, we don't want to be blind. We don't want to introduce risks, right? So, with this in mind, we need to have a very large team with a diverse set of eyes looking in at each opportunity, and then implement this opportunity in a very rigorous and thorough approach to make sure that we maximize the opportunity without introducing any risk. So, what do I mean with this? So, when we introduce, for example, comprehensive genetic testing, where we look at 7,000 plus rare diseases and all 20,000 human genes we may also identify other factors in the genome which can have a clinical implication, and for that reason, we need to be really clear with the family and the patient that we consent them in the right way. So, for example, if I have a child who may have cancer and I want to do a comprehensive genetic test to understand why the child is sick and has cancer, we don't want to identify other factors which can later describe risk or predisposition for, let's say, a late onset neurodegenerative disease. If the family would opt in for such a test that we find, we also report incidental findings. That is the decision of the family, and they consented for it. But if the decision was only to get information about the cancer risk, then we should only disclose the cancer risk and to make these decisions, design these consent forms, the processes, and overall the clinical and scientific evaluation, and also develop the workflow how to introduce this because it takes time. Not everything is reimbursed. We need to have all the stakeholders on board, including medical genetics, compliance, risk assessment, and on top of this, genetic data can be very big. It's one of the biggest types of data. If we want to look at the data maybe in the future ourselves again in a framework, we need to take this all into account, have discussions around this, develop best practices, and then introduce this. It's not that we have a new test and we can get directly going. And often this integrates also a lot of certain level of exploration and learning, because again, you cannot just ChatGPT or Google it and find a recipe how to do this. There's some learnings from other institutions for some of these aspects, but for many we need to tailor it also to our institution, to our own risk profile, and our own culture, and the Cook Children's way to embrace these innovations, but still have the best outcomes in mind. So every path I go towards, it's always many, many, many steps which need to be figured out and have many stakeholders' involvement to make it work, because the goal is here really not to focus on five patients, which one doctor sees and just wants to make it work for their specialty clinics, where they may be an expert in. Everything needs to scale, so it needs to be a system in place which then can be supervised digitally and by experts. But in the end, it should work without hiccups, even in West Texas, where we have pediatricians for certain aspects of it, and not only here at the main campus, where we have a big team. So everything needs to be done very thorough and step by step. And the only way to really scale is through technology. It's not through people. So people needs to have the oversight, need to benchmark the system, need to rigorously over and over test if it's working. But at the end, we need to scale. What do I mean with this? Medical knowledge is literally doubling every eight years. And this field of precision medicine for disease. -- and I can speak from this as a scientist -- I have discovered many epilepsy-associated genes, where each gene has their own spectrum. Where people have epilepsy, but they may also have autism, movement disorders. They respond to specific drugs. They have adverse effects for other drugs, which are maybe often commonly used if you wouldn't know the genetics. So for each of those diseases, they were undiscovered and looked as many many other rare severe epilepsies. Today, the gene, and there's for example, 400 publications on that gene alone, and we have for epilepsy more than 1,000 genes which can cause epilepsy. So basically, each of those genes has between five to 1,000 publications, and only these publications were published in the last two to 15 years. There's no way that a human can utilize all this information and bring it into care decisions. Just simply, there's no reimbursement path, and so on and so forth. So what we need really is having experts which are technology enhanced, so that the knowledge comes to the expert. The expert can critically review it, and then in a larger group of many diverse experts can decide what needs to go into the system and what is not, and when it's ripe for moving forward. Otherwise, we cannot embrace the new opportunities all this research is giving us. We cannot wait for textbooks. There will never be a textbook of 1,000 epilepsy genes which someone has to memorize, and no one has the time. Physicians are there to care for patients; they are not there to read every day for nine hours publications. So the only way to move this forward is if we bring knowledge to the system, and the system has the knowledge prepared for critical review that people can use it in care decisions. And this is a completely new way of learning health care system, where you on the one hand learn from the research, so basically other patients which others have summarized, but also you need to learn from within, from the patients you have seen or your system has seen, and into the next patient. And only if we accomplish this, and this is something which we're building from scratch, right? So, and then we can scale up, and because we can make non-expert to an expert, and or connect them with an expert to increase the care, or even outside of the individual expert's realm, or even what would happen if we would have one expert, it's the global leader. That person leaves is retiring, or suddenly the knowledge would be lost, and that we don't want to be in this situation for our patients. We need to digitalize knowledge at least to some degree, and this is what we are building now. 00:13:32 Host: One of the most critical points I've heard you talk about in your work is families becoming a larger focal point in the care process. What does that mean, and how does that change how we approach medicine today? And most importantly, why does it matter so much? 00:13:48 Dennis Lal: I can speak very specific for neurodevelopmental disorders and severe epilepsies because here I'm really active in global research. I'm leading a lot of activities globally, and I'm also advisor on 30 patient organizations from a research org on the medical advisory board, and we are we're together with Scott Perry and Dr. Christos Papadellis. We are developing also no specialty clinics and a lot of research here at Cook Children's. I'm actually driving this afternoon to a rare disease conference, the CACNA1A conference, where I'm also on an advisory board, and we are doing research at the conference, and in 10 days we are going with my whole team to the Families SCN2A conference. So the interesting thing is, many people with rare diseases they often receive symptomatic care. So for people with, for example, SCN2A related disorders, the child may have a lot of seizures, and they would go often to the emergency room. They would receive the anti-seizure medication. Then they may see an epileptologist regularly, and none of the drugs will work. Some drugs work a little bit temporarily, but that's it. But the issue is that children also have a lot of problems with eating food, digesting it, or GI issues. They would have, often, very severe communication problems, and then they may even have behavior abnormalities. And some of these symptoms are relatively subtle. And if the provider would only focus on symptomatic care, which often happens, they ignore it. But families would feel this, right? So in a 20-minute visit with their neurologist, who may not be trained on the genetic lens of the disease, the other symptoms would not be much taken care off. And so, what I mean by that is that specific referrals, which often can be surveillance referrals, for example, in a child where we now that by the age of four or five years, 80% of the children will have a movement disorder problem, and the child is still like two three years old. Typically, symptomatic care would mean that the epilepsy is taken care of, but there's no referral to a movement disorder specialist or occupational therapist. However, in multidisciplinary specialty clinic setting, what we are, for example, here having at Cook Children's with Scott Perry, he would already do the referral to his colleagues, and one would already set up the child for a better course of the disease. Because what we have learned in research is, the earlier you intervene with therapists, for example, in this case, occupational therapy, or if it's for communication, speech-language therapy, the more you invest in these therapies, and the earlier you invest, the long-term outcomes will be different, but this requires really there's proactiveness in working with the disease, and currently and often the situation is that the only way that there is proactive care is that the family becomes very educated on the disease. They see the genetic finding in the tests in a young child, for example, and then the family needs to read up on this. They need to connect with the patient organization. They need to read scientific papers to understand what is about to come, because the system and the providers were not empowered yet to be proactive. So everything is reactive, and this is something what should not be the case because these are already families who are struggling hard, who have a severely sick child, and have to battle with all the costs, with often lack of sleep, with a lot of emergency room visits, with a lot of drugs they have to manage for their child, and in general, just taking care of their child. They shouldn't, in my opinion, spend a lot of energy on understanding where is the next provider at which age specific therapists should be referred to, so that their child has, in 10 years from now, the best outcomes. And so the reactive care for rare disease leads to the situation that parents often they read into the disease because their children, right? So whenever they have the chance, and they're often noticing that from the time they have been diagnosed and saw the finding in the genetic test result till the next visit is scheduled in a couple months from now, they read up so much knowledge. They watch all these YouTube videos from family stories, or a lot of patient organizations have amazing content, also tailored for families, and they have more knowledge than the physician on that given rare disease, not on care in general, but for that rare disease, and they get dissatisfied in ... in the care they're receiving, and often this leads to a situation that they seek care elsewhere. So they move to many places, and then they have to travel with their severe sick child and take on all the costs of moving out of state, and this should not happen. And at the same time, when I was younger, I was also observing this phenomena already, and I was already leading specialty clinics or directing them. I would never see many patients, but then I would never give medical advice because I'm not trained in this. But I would already observe these phenomena, and I would always think in the past this is because the physicians don't try hard enough, to be honest. And this is wrong. What I learned today, because science is moving so fast ahead, and many people didn't even receive the education about the importance of genetic testing. So our whole educational system for precision care, for tailored care, doesn't keep up with all the knowledge we have in research. So the distance from new knowledge in medicine, and particularly for severe rare diseases, again, which make a large chunk up from our patients, to action in clinical care is minimum. So it's basically something ... there could be today a new paper out where they describe which intervention worked in 50 patients of that rare disease which have been collected globally, and this might be the first paper out there ever. And if a physician would know about that paper and they see tomorrow a patient like this, this is the best information they can take on to inform the family and potentially in their medical evaluation, consider maybe some of those referrals or other recommendations. The chance that this will end up in medical textbook is minimum, if at all. It will be in very specialized magazines, and this is in five years, 10 years from now. But families are suffering today, so we need to have physicians who can critically ingest medical knowledge, and then based on their medical training can call for applying interventions from research. But again, epilepsy alone is that example. There's more than 1,000 genes. There's every day hundreds of publications. We cannot expect that our physicians and, in general, the health care system can keep up. We need to develop frameworks to use this, and they are digital. Otherwise, families will use ChatGPT and tools like this, and they don't have the medical training to critically use them. And this is the new frontier we are having. There is knowledge, but not all knowledge is good. Some studies are better than others, and certain things may make sense for patients which have been reported in a research publication, but they will not make sense for that patient which we have in front of us because there are certain circumstances which only a trained medical professional can judge at that very moment, and we need to bring this all together. And so the key is still physician, but empowered with all the knowledge there is today. 00:21:03 Host: Let's talk about rare diseases. There are so many, yet access to information on diagnosing and treating them currently is limited. I've heard you use the term data, data, data, and you're looking to a future where databases become more informative and accessible to primary care and specialty physicians. And if so, what is it going to take to bring this to fruition, and how do you envision this ... its use? 00:21:30 Dennis Lal: When it comes to diagnostics, we're actually in a good place. Already in the neonatal intensive care unit. For example, I think the diagnostic yield, so that's what we call how often a genetic test can deliver a diagnosis, as I think already greater than 30 percent. And there have been many studies that if you would do routine whole genome sequencing, that you can diagnose again, like one in three to half of the children just by the genetic test. And the interpretation of the test is a different process. So the test, when you order it, you send it to the diagnostic lab. And at Cook Children's and in other places it's often a commercial diagnostic lab, and they will provide you the classification of the test. And often it comes back positive. So that way you get the diagnosis. The clinical interpretation is up to the provider, and the clinical interpretation is very strongly aligned with the genetic finding, but can also sometimes be overruled or enhanced. So I think in both aspects we are very good. So there's a lot of things happening, but we still could increase the rate of genetic test ordering in the NICU, but also in many many children with many many other diseases, where they are typically not seen in the neonatal intensive care unit. For example, there's the guidance by the American Academy for Pediatrics, which says that every child who has developmental delay, intrusibility, autism, and then there's other guidelines which suggest that every child with congenital abnormalities or seizures, they should also get a genome. And these children are not in the intensive care unit, and their route towards a test could be faster if they would receive the genetic test or the test order, for example, through a pediatrician. However, pediatricians are not trained in genetics at all, right? So this is, for example, where we will team up with medical genetics to develop pathways which enable the scale, because only few people will see a medical geneticist here at the moment, and people who are members of Cook Children's, but for example, in West Texas, they shouldn't need to drive all the way to get to genetic diagnosis. There's also telemedicine, and there's also other ways how we can scale the approach. So the genetic test order is one part. How to basically start the tailored care, and also flagging people who should get a genetic test digitally, and educating providers about the knowledge who should get a genetic test is the first part of the tailored care or the precision care, and we are in good shape. So I think across the U.S. the diagnostic odyssey, meaning until you receive the genetic test, which explains the reason why your child is sick, was up until recently eight years. And you know you can imagine this is traumatic experience. If, for example, I just personally think I would have severe headache, and it would take me eight years to figure out why I have this, that would be not a good experience. And we're not talking about headache here. We're talking about children who have really, really bad diseases, where the family is forced to get from one assessment to the next because they desperately want to see their child improving. But the number from eight years is reducing now to three years, which is still bad time. Knowing that for many of the diseases, the moment you can categorize them by gene or other genetic finding, we can do something, right? So at least we can link them to patient organizations where they have a community. Where they're continuously educated, where there are many other families who go through the exact same journey. But my gut feeling is that we are getting better at this, and it's just a matter of this organically will improve because the knowledge of that genetic tests are powerful is increasing. But of course, as part of the precision health program, we will focus on this more through education and also digital enablement, but the other thing I think where we have the biggest opportunity, which is not tackled much at other institutions, is really to digitalize care pathways. For example, one of the specialty clinics which we have here, where Cook Children's is famous for, is Dr. Perry's Dravet Clinic. So Dravet syndrome is a severe form of epilepsy where the children have high mortality risk due to the epilepsy, and also the communication abilities are severely challenged to the degree that typically children who have Dravet syndrome will not be able to live alone later on, even if the epilepsy reduces. So they have severe challenges to communicate and interact independently, and on top of this, many people have movement disorder problems and sleep problems. It's a very severe disease. So, if a child has a first seizure, let's say by six months, and it would receive a genetic test result, and it would be positive for SCN1A, and there's a specific type of mutation, the probability that the child will develop Dravet syndrome is basically 100%. So with that knowledge, a person like Dr. Perry could initiate a lot of surveillance and not preventive but modifying pathways. And for sure we could enroll this child in I think one out of three clinical trials we have going on here at Cook Children's at the moment, so there would be a lot of power in that diagnosis and that certainty. Even that has been only one seizure, that this is very likely to be renovated syndrome. This is a very powerful information which comes with a very experienced provider who knows this and would be very proactive in that sense. However, if the same diagnosis after the first seizure would have been made by someone who is not experienced with Dravet syndrome, hasn't seen more than 100 patients, like Dr. Perry has, it actually is very likely that they would not be very proactive about this, and why not? Because around about one in five children will have a seizure as a child, and this will resolve, and there would be no negative aspect of this. And also, there is another disease associated with the gene SCN1A, which is called GEFS+. This is a very mild form of seizure disorder. You have a seizure, but you will not develop any form of delay. So, for a clinician who doesn't trust or is not trained in using genetic information, they wouldn't know that certain mutations you basically 100% get Dravet syndromes. You need to understand this. Here, medical genetics can help because they can read the literature, but they wouldn't have the same knowledge and best practices like Dr. Perry would have as an international expert. However, Dr. Perry he can set up certain rules in the system that anyone who gets diagnosed with Dravet syndrome for specific type of mutations could follow Dr. Perry's best practices, or at least we could agree that the physician who is seeing such a child and with such a mutation and seizures should see Dr. Perry directly, should automatically get recommended a referral to Dr. Perry, so that there is no need of word of mouth or some kind of connection to Dr. Perry. And this is something where these digital care paths, where there is less room for individual provider to provide differences, where we have the biggest opportunity to maximize today the best care for genetic disorders, where there is already a lot of knowledge in the literature. 00:28:55 Host: So, do you foresee, like at some point, one centralized database where anywhere in the world somebody can put in certain parameters and find some results that they can then look at their patient with? 00:29:10 Dennis Lal: Yeah. So if there's a gene and you know that all the experts agree that this gene will lead to a specific disease and this disease has specific needs or responds to certain interventions a little bit, or certain ones very good, or for certain drugs there has adverse effects, there should be like an international best practice database, right? And this is actually not existing. And the best practice guidelines they require that a group of experts agrees on something and that they meet together often physically and then updated regularly. And this is only happening to less than 1% of the 7,000 plus rare diseases, because it requires a certain level of commitment. And typically, this type of engagement is not financially incentivized, unfortunately, at the moment. On the other hand, there is a certain level of information already in the literature, in the scientific literature. And reviews, and this is where good genetic counselors or geneticists can support the neurologists, and in my case, neurologists, to bring this together. But there's still a lot of work to be done to get the information cleanly organized, and then in a format that can be integrated in the health care system to the degree that it can be judged with the medical history of that individual, and because, again, genetics is one aspect, there's many other aspects which need to be factored in. So at the end, it's like in a tumor board or in a patient management conferences for a high-stakes intervention like surgery, there needs to be many providers be involved and have this discussion, and this is also what we are establishing at the moment. These kind of frameworks where we have interdisciplinary boards for interpreting genetic findings in ... in the specialties together with the experts. Because often in an individual gene there can be actually multiple genetic diseases depending on where the mutation is located, what type of mutation, and the individual biomarkers such as echocardiogram, an EEG, an MRI, or certain liquid biomarker can actually inform which version of the disease is combined with the genetics. So that all said, how I see what we will build here is we need to have a learning healthcare system. We need to have a data strategy and database to learn from our own patients, but at the same time we also need to keep up with the continuously growing literature and best practice guidelines, and for that we need to also ingest information from continuously developing databases. They're all fragmented. There's databases for gene one. There's databases for disease X. We need to aggregate information from there and then combine with the knowledge which we have locally, and then have an expert group developing processes extracted from it that we can integrate, or at least have a resource where we can have our experts access to that they don't need to look at five or 10 different resources to make a decision that we can make it easier. That a patient investigation for 20 minutes doesn't end up with just 20 minutes of clicking to get to a point. That you can use these 20 minutes of prep time for a provider really to get the critical information out they need to make a care decision. And so that definitely requires data strategy to develop precision health at scale. 00:32:21 Host: So your program is launching with a focus on neurology. Why and how will that ultimately lay the groundwork for expanding into other specialty conditions? 00:32:32 Dennis Lal: So the focus where we develop a lot of things from scratch is really neurology, but we're also trying to enhance together with Dr. Ray, for example, oncology. So there's already a lot of beautiful things going on in oncology. So, to the best of my understanding, as many, if not all, children are offered to participate in clinical trials. A lot of drugs are repurposed, and a lot of frameworks of really cutting-edge care have been developed. And in oncology, it's really to digitalize and scale up these frameworks, but not to invent them. And oncology as a field is already quite ahead in this space. Many institutions have tumor boards, do drug repurposing, and there's a lot of precision drugs already approved, which act on the gene or even a pathway. So there, it's really to facilitate the framework. However, for neurology as the basically the first disorder beyond oncology, reflecting the 7,000 plus rare diseases, is where we have to develop things beyond Dravet syndrome from scratch. So there's a couple specialty clinics already, but they are not beyond a single syndrome. So here we are biased towards neurology because we have our most successful researcher, Dr. Papadelis, who is also NIH funded, really unique. We are building this out. Who is an epilepsy researcher, and he is also the research head of the Center for Neurology. This has an advantage for us because we can not only provide precision care, but we can also perform research with every patient and learn from our specialty clinics, which can generate knowledge, which can globally improve the care for patients. So that was very important to have a strong researcher also with us. So then we have Dr. Perry, who is not only an expert for Dravet syndrome and is leading a lot of the clinical trials in that space, but he is also the director of the center and he's the second epilepsy researcher, which is strong. But also he is the president of the Child Neurology Foundation. So every activity which we make successful here at Cook Children's, we have pathways through the Child Neurology Foundation to move beyond Cook Children's and so have a larger impact nationally and globally. On top of this, Dr. Perry is also a key leader in the Pediatric Epilepsy Research Consortium, which he was founding partner and recently also the president. And here again, there's a network of I think 100 plus pediatric epilepsy hospitals, where we can move our learnings also beyond Cook Children's,. And the last reason why neurology is strong is because it happens to be that I'm also an epilepsy researcher. So we have then basically a trio of experts on the one brain imaging and physiology, so everything EEG and MRI related, and with Dr. Papadelis, then we have Dr. Perry, who is a clinical expert, and then we have me who is a genetic and data expert, and I also happen to be NIH funded and have a very strong publication record. And it happens to be that I also know Dr. Perry and Dr. Papadelis for a long time, which makes getting started in that space relatively straightforward because the whole team is already very research trained, and we all speak the same language, and we can establish a lot of pathways forward because we understand the needs all three together very well. 00:35:55 Host: As we stand at the precipice of truly putting patients at the center of medicine, what does the future of precision health hold, especially for children and their families, and the future of health care? 00:36:08 Dennis Lal: I think the most important thing is that we offer the families to participate in clinical trials as soon as possible. Like we already do in oncology. We work with Dr. Stigall in the Research and Administration department, which is basically running all the clinical trials, and where I'm located, we are really focusing on expanding the clinical trials. So at Cook Children's, it should become normal that every time there is a disease where there is no solution in terms of care, that we bring all the tailored care experience to the family and offer also the families participate in a clinical trial, which may bring the solution to them. So basically, that we are the first to offer our patients to be part of the next generation of therapies. On the other hand, we really need to become proactive in care. So we should reduce the burden of families that they have the need to know about the disease. Families should, in my opinion, have all the opportunity to learn about the disease, but they don't have to. I don't think it is the right framework that your child is striving that you need to get the knowledge of a medical doctor or a scientist. This should be removed. It should be the job of the health care system to serve your community and have the families focused on loving their children and really helping them with everything outside of the hospital. What is ever needed for the sick children, and they don't need to understand the disease to the degree a large team in a very technologically supported system can do, and this is something we will focus on, and which also others are focusing on. This is not a unique strife, but now with technology, we are really the first time in the position that we can achieve this and really try to bring the care for children or families with complex rare diseases back to the hospital. At the same time, we also should develop frameworks to really care for our families and children when they're not at the hospital, because the moment we rely on families to observe a new symptom and come to us or to monitor what is going on with their children, then we really put again the burden on the families. With a lot of technology and approaches, really good strategies, which we can come up as a integrative team, we can also check in on our families and ask them, "How is it going and, is there anything you want to share?" And with technology we can reduce the burden also from on the providers to do so, so that the next time the family is scheduled, that they don't have to remember the last six months what was going on, and because in a short check in with a nurse or medical provider they may not remember everything, but might still be relevant for the disease because rare disease is continuously evolving. And so we really, I think, need to envision care differently how it's done today. Again, it's very reactive, but we have now the technology at hand, and here at Cook Children's, we have the willingness to embrace this in a very thoughtful way. And for example, I'm here since six months, and I'm running in so many problems in executing my vision, or our vision. I think it's not my vision, which is beautiful because everyone wants to get involved. Because I may be ambitious in what we want to achieve, but we need to have the legal, the chief medical information officer team, the regulatory team, many providers who have different views on the individual disorders they are caring for, really involved, and they are really all involved at the moment. Also, medical genetics, of course, so that we can achieve this, and I think for many other systems, this would not be possible because you need to be agile enough and not build out yet. You need to be in a place of significant growth and embracing a solution where the path towards forward is not so straightforward. And I really have the feeling that we are really embracing this, and so that's why I'm very hopeful that we will achieve a better future for the children we have here, and we're going from a system a way where there is an individual expert who is serving the patients they are seeing, and really, I think, unleashing the mission of Cook Children's, where we really serve every child, and the scale is really technology. And again, it's I don't want to talk overly about this, but technology is also risks, right? So things often don't get so fast. I like I wish for, but fortunately, we have really strong support from our legal and compliance and regulatory teams who really keep an eye on this-that we do this the right way, right? So we don't want to be an overly fast adopters and then get burned and then shy away. We really want to be successful, and with the success, getting more attention and resources to really build this out. And we only can do this if we do it the right way. 00:41:22 Host: Before we wrap up, is there anything I haven't asked you about, or anything that you want to add? 00:41:27 Dennis Lal: When I speak, I'm always worried a little bit that it sounds that it's too much me because it's not at all. I really want everyone who listens to really think about this and consider that everyone can play a part in this because it's really unique time we are in, and it's often not discussed enough in the media. Literally, every rare genetic disease, which likely make up one in five children and more in our NICU, and the children who are always hospitalized, it's the first time in history that we can diagnose them. And if you think about this, that genetic diseases are also present in any higher species, like fish or even your cat and dog. They have the same diseases like our children have. Because these genes they are playing essential roles in every higher organism, and the same mutations which can cause, let's say in my case, a severe epilepsy, they cause severe epilepsy again in a cat and a dog. And because these genes are so important for brain function, same for liver function, same for heart. So, if you think about time, we have basically 300 million years where there's no way to diagnose this, and since two years, the insurance paying for it. Two years, 300 million years versus two years. This is just a scale. No, no human can see what the opportunity is. At the same time, you follow if you type into Google CRISPR new therapy. If you type in gene therapy. If you look at success stories on YouTube, and it's the first time where we can not only diagnose, but we can already in clinical trials, and for few diseases even in care, cure these diseases literally. There's this best example for spinal muscular atrophy, where the first type of genetic therapy was approved five or eight years ago, and for the first time in history, the children would survive. So that is already game changing. But what people learned is that, "Hey, what happens if we give the drug a little bit earlier?" And this is a disease where a child would never sit independently. And there have been studies last year when if you give the drug before the milestone is met, the children will sit. And to the degree that there was a study last year which was super famous, where the mother got implanted for an egg which carried the mutation, and they gave the therapy before birth, and that child is doing really well. So we are really living in a world where, if you do the diagnosis, it's not the clinical, the genetic diagnosis. There is solutions these days, and even if it's maybe not today, but it might be tomorrow. But it comes with a lot of challenges in clinical workflows, in education, and so on. So I would just argue, everyone, so just embrace this opportunity, this unique point in time, where for literally thousands of years in human history there was no solution. People would just give up. We have now the first time the opportunity where we can match families with patient organizations, and where there is a really good chance that there is a clinical trial, maybe not at every institution, but at Cook Children's, we are trying now, really, to get all these clinical trials going and develop these specialty centers and try to support our clinicians. But at the end, it's just everyone plays a role in this, and just getting the word out that people … you may have a family member who has a severe disease where you may have given up, or there's a lot of people who live in intensive care facilities or assisted living facilities where people did receive a clinical diagnosis 10, 15 years ago and they didn't receive a genetic test anymore. There's a lot of opportunity where it's really important that we get our communities tested, that we can generate databases that when the new therapies are coming or the trials are coming or the drugs are approved that we can give them to our children. And in general, everyone who is a little bit younger or just still interested in learning, particularly in the medical field I would really go all out on understanding genetics and precision therapies because if you are not comfortable with genetics, you will be the observer of the new evolution of therapies. You will not be in the driver. So, in general, genetic therapies and genetics, which should always be done together with medical genetics in a team approach, but still often for the specialties, the treating provider is not a medical geneticist. It's the person who monitors the patient, who looks at all the biomarker, and that is often a cardiologist. This is the neurologist. This is the endocrine expert. You know, and so really embracing as a young physician or even old physician who is hungry and wants to embrace these new technologies, it's really important to learn about this, and I would not limit this to medical doctors, because medical doctors often spend like just a small portion of time with the families, and a lot of the nurses and also social workers spend a lion's share of time with families, and families have so much questions, and they are now with ChatGPT and all the AI, they come up with a lot of hypotheses and ideas. Some of them might be right, others might not be. And if we already have our whole medical team genetically enhanced in terms of knowledge, we can provide care on multiple levels. And there's a lot of opportunity also in that space. 00:46:40 Host: That's fantastic. This is such an exciting time in healthcare. It really is, and I just wonder what Hippocrates would say today. Dr. Lal, thank you so much for being here today. This has been really informative, and also, like I said, very very exciting. 00:46:59 Dennis Lal: It's the best time to have a rare severe disease at the moment. It's just never good, but always when I talk to families, I would say this is a really good time to be hopeful. 00:47:09 Host: Thank you so much for being here today. 00:47:11 Dennis Lal: Thank you. 00:47:12 Host: And for our listeners, if you'd like more information on research and innovations, visit cookchildrens.org. 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