Children’s Mercy Research Institute has been expanding its efforts to understand the genetics underlying rare diseases. Earlier this year, it opened a new home in downtown Kansas City and at the end of last year launched Genomic Answers for Kids, a first of its kind pediatric data repository and the institutes flagship research initiative. We spoke to Tom Curran, senior vice president, chief scientific officer, and executive director of the Children’s Mercy Research Institute, about the program, its ambitious efforts, and it focus on translational research.
Daniel Levine: Tom, thanks for joining us. We’re going to talk about Children’s Mercy Research Institute, it’s expanding effort in understanding the genetics of rare disease, and your Genomic Answer for Kids program. I’ll admit to a bit of a coastal bias. I think there are many listeners who may not think of Kansas city when it comes to thinking about cutting edge genomic research. Perhaps you can take a moment to explain what Children’s Mercy Research Institute is, and its focus on translational research?
Tom Curran: Absolutely. I will confess having lived on the East and the West coast, I shared your bias until I actually came to Kansas City, and I urge all your listeners to come to Kansas City, it’s a wonderful place. So, the history of Children’s Mercy goes back over a hundred years to the two Berry sisters, one of whom was a dentist and the other was a qualified physician who founded the hospital. It was pretty rare to have those qualifications for women back in those days. They particularly wanted to serve the needs of underserved children. From the very beginning, they had a statement that said what they really wanted was to have a research laboratory in the hospital so children’s diseases could actually be studied. So, they understood long before it became widely known that you need to study diseases in children in order to help sick kids. The reason is that children are not little adults. They have unique diseases and considerations, and when it comes to rare diseases, the vast majority impact in childhood. Although the focus of Children’s Mercy through most of his existence was in delivering the highest quality pediatric health care, there was an interest in research and there were pockets of excellence. Children’s Mercy had one of the first dedicated pediatric clinical pharmacology programs, which over a period of 20 years built a real center of excellence. We actually founded one of the first pediatric genome centers dedicated exclusively to children. That predated me joining Children’s Mercy. When I joined in 2016 to develop the concept of a research institute fully embedded in the children’s hospital, genomics was always going to be a large part of that picture. At the same time I joined, Children’s Mercy recruited a new lead for the genome center, Tomi Pastinen from Montreal. He has launched this Genomic Answers for Kids project that you mentioned. So, we’re really continuing a long-term trajectory of Children’s Mercy, and we’ve accelerated the process by building this state-of-the-art research facility tightly integrated with the hospital.
Daniel Levine: There is a great focus on translational work. How do doctors and researchers interact with each other as they work with patients?
Tom Curran: You put your finger on the absolute perfect question. I have a history of working in pediatric translational research that goes back to the mid-nineties. I encountered the conundrum that researchers and clinicians work for the same purpose, but they do it in very different ways so they need a translational device to bring them together. So, over time I figured out how to create partnerships and the partnerships are really key. Everyone is in a sense equal around the table, the caregivers, the research technicians, the investigators, the faculty, and even the administrators–they have a major role to play when it comes to complex pediatric disease. The group thinking and the team approach turns out to be the absolute key. So, in designing a research Institute, the more thought you put into enhancing those encounters, and providing environments where physicians and researchers can talk, and including parents and families in that conversation, is really key to making progress.
Daniel Levine: In February, you opened your new home in downtown Kansas City, a nine story, 375,000 square foot building. Before we get into what’s going on inside the building, I’m wondering if you can tell people a little about what they see on the outside?
Tom Curran: In research you come up with hypothesis, you design experiments to test them, and sometimes things happen that were unexpected and you have a serendipitous finding that leads you in a new direction. Well, the facade of the building was exactly that. When the architects presented me with the design for the building there was an arbitrary design in light and dark glass panels on the facade. It actually struck me as a familiar pattern. It looked exactly like two Sanger DNA sequencing gels. So I asked the architect, “Could we move some of the panels around to create a different design?” And she said, “Absolutely, you can do that.” So, I moved them around, and at no cost, the architects were able to plan the building that took on four of our patients’ DNA sequences. I reached out to our investigators and they came up with sequences that would illustrate different aspects of pediatric disease. Then the architect mentioned that she could put LED lights behind the windows that could light up at night, and this was Jackie Foy from BSA LifeStructures. We were able to show not only the DNA sequence, but we can highlight in a contrasting color the rare variant that underlies the condition that those individuals had. One of our subjects volunteered to go public with his condition. His name is Ben, and he actually flicked the switch to turn on the first light on the building. It demonstrates his DNA sequence, which is associated with a variant that affects medications that he was taking for ADHD. It created a life-threatening condition that was easy to resolve once the underlying reason was found by simply reducing the dose of his drug, because he was not a high metabolizer and once the dose was reduced, the side effects went away. So, the message is twofold. We’re proclaiming to the city, and indeed to the world, that we work on the conditions and diseases that patients bring to us and we treat every child as an individual. This is the basis of precision medicine. The second message is internally in the building because investigators in the building are bathed in light that’s filtered through the DNA code of our patients. So they know every day, why they’re coming in to work and put the purpose of what that ultimate research is.
Daniel Levine: In October, you launched Genomic Answers for Kids. This is billed as a first of its kind pediatric data repository, and the flagship research initiative of CMRI, what problem is Genomic Answers for Kids trying to solve?
Tom Curran: It is actually addressing several problems. Let me tell you the history of how we got there. When Tomi Pastinen joined Children’s Mercy, he really wanted to get involved in what he called bedside genomics. He wanted to bring genomics right to the patient. He brought in a lot of expertise in running large genome projects and technical expertise in various aspects of genomics. So, I got together with the head of philanthropy, Jenea Oliver, and we challenged him to propose a large-scale project. We knew we could get the Kansas City community behind us in terms of fundraising. He came up with the idea that the issue was that we didn’t have a sufficiently large database for pediatric-specific disease, particularly rare disease in children. The problem with a lot of studies is that they use only de-identified materials. So, the information can’t be returned back to the patients and families. We struggle, as does every children’s hospital, getting insurance companies to pay for various genetic diagnoses. This can lead to a terrible odyssey, where families spend years going from clinic to clinic, hospital to hospital, test after test, until they sometimes never end up with an actual answer as to why their child has a certain condition. By creating a large-scale research project that has the goal of recruiting 30,000 patients, and a total of 100,000 individuals when we include parents and siblings, we can provide clinical grade sequencing done under CLIA cap conditions to families and cover the that as part of the research cost. To meet those costs, we went to our donor community, and they stepped up to the plate. To date, we’ve raised more than $17 million to launch that project. So the project was launched and, even in the time of COVID, has already amassed over 10,000 genomes.
Daniel Levine: This is an ambitious effort to sequence children and their family members. How many genomes are you hoping to sequence, and over what period of time?
Tom Curran: Over the course of seven years, our goal is to sequence a total of a hundred thousand genomes using a variety of technologies. As you know, there is not just one genome, there are multiple genomes and different ways of looking at those genomes. The idea is to get the right technological approach for the right condition and individual. We’ve already consented more than 2,200 families, with a total of 2,600 patients enrolled in the program. From the first 10,000 new genomic analyses, we’ve made more than 250 genetic diagnoses and identified several new disease genes just in this first year of the program. Some of the individual stories are just amazing. There’s one family, an extended family with multiple members, who got their first diagnosis 50 years after the first quest to find out what was wrong with an individual.
Daniel Levine: I know you just announced that you’re expanding the number of large-scale whole genome sequencing as part of your collaboration with Pacific Biosciences. This is for their Hi-Fi genome sequencing systems. What does this expansion mean to your capabilities?
Tom Curran: It’s a pretty big boost. In fact, the relationship with PacBio is not a simple vendor client relationship, they’re really partners. They’ve developed analytical approaches and they’ve helped optimize the whole sequencing path. It’s been really invaluable to work with them. Their technology is one of the so-called single molecule long-read sequencing approaches. It gives a very different kind of product that allows you to look at fairly large-scale gene rearrangements, which are often missed in the more standard whole-genome sequencing approaches. We do believe that this technology still has ways to develop and grow, but we want to be in on the ground floor pioneering its application for these children in need. We want to take kids from the back of the line and put them at the front.
Daniel Levine: What do you think this technology will mean for the discovery of new variants?
Tom Curran: Well, it will increase the hit rate. We already see that even in some of these initial applications. A lot of sequencing programs focus entirely on the coding region or they focus on target genes. By taking the whole genome approach, we can uncover things that lie in the spaces between genes, for example, and identify some of the really tricky rearrangements which don’t show up very well on other sequencing platforms. So, we think the hit rate is going to go up. We think the quality of the sequence is also very interesting. When you see these reads laid out and you get a chart and you can see the overlapping reads, it really lends itself to other kinds of analyses. We would come in on top of that, for example, with a methylation pattern with other epigenetic approaches. We would take some of the results that would come out of the PacBio sequencing and use them in other genetic screens for functional studies to take us to the next level. Of course it works very well in combination with RNAseq in terms of trying to understand patterns of expression that may be influenced by gene rearrangements.
Daniel Levine: I think there are many parents of children with rare diseases and adults, too, who think, if they can only get sequencing performed, they’ll have the answers they seek. Even though we’ve seen improvements in the ability of sequencing to diagnose patients, what do you see as the biggest barriers that still sometimes result in no conclusive answer? And what do you think will change that?
Tom Curran: The sequence is not the end. In many cases, it’s the beginning. Families do understand that once they get involved in this journey, there are tricky issues that exist in understanding the genome, that you only see when you start looking in great detail. For example, we use a reference genome that everybody knows is not complete, and is not ideal. Ultimately, you would like each family to be their own reference genome. You build a full genome based on these long reads. We’re not quite able to do that in every case on a regular basis, but I think that’s where it’s going to end up in the future. Frankly, you have to acknowledge that there may not be a simple answer coming from the genome. We are not necessarily focusing on single gene diseases. We are focusing on children in need that present with a condition. That condition could be attributed to a collection of gene variants. Finding out how those different gene variants combine to create a condition is a really challenging piece of science, and that may be required for some of the conditions that we see. There are still regions of the genome that are, even with the new technologies, very hard to sequence through. Sometimes you get results that are open to interpretation. If a disease alteration lies in one of those cloudy areas, that still doesn’t give a very clear answer. Another answer might be that maybe there’s not a genetic explanation for this disease, and that’s an answer in itself. What if there’s an epigenetic problem? Well, you still need the genome to understand the epigenetics. So, what the initial sequence analysis does for you is rule out certain other options and allow both the clinical team and the research investigators to focus on where that problem may actually lie. I think that the most important aspect of this large-scale project is that we’re bringing this high-level technology to bear on the pediatric population. In a sense, we’re pioneering the integration of genomics with the medical record. The children in the study will always have this reference genome to go back to for the rest of their lives. If they have additional sequelae of their condition in later life, they have a starting point and it’s not going back to scratch. I look at this as an ongoing project that is bringing medicine to another level. In a sense, we’re pioneering the future of all of medicine by working on kids in need.
Daniel Levine: You and I have spoken in the past about data sharing and CMRI’s commitment to it. As you build this data repository, what are the plans for data sharing?
Tom Curran: Data sharing is our bread and butter. There is no question that there’s an obligation to share all the data that comes out of this project. It’s also the best way to come up with answers and solutions. In fact, as soon as we find a variant in a family, we look to the literature and find who’s working on this and has specialty knowledge. We reach out to those folks and engage them in trying to understand what the sequence is telling us. We may have information within those sequences that someone else would recognize, and we don’t recognize. So, the more we can make that available, the more eyes we get on the problem, the closer we are to providing solutions for families and patients. Of course, we’re contributing to the standard variant warehouses, the genotyping, and whatever clinical information we’re able to share. We’re also setting up a platform that allows, as close as possible, to real-time sharing of detailed information. This would require investigators to have IRB approval to get access to the clinical information that they need to unite with the DNA sequence information. It’s easier for us to share the genomic sequence information without the detailed clinical information, but at some point investigators need access to that. So because we are building an identifiable database, which is clinically and HIPAA protected, you need to go through those barriers. That’s because the quality of information is there. I believe this is the future of research and you need access to all of that clinical information.
Daniel Levine: And as a researcher in this world, why does that matter so much to making advances in rare disease?
Tom Curran: With rare diseases there are many conditions we don’t even have a name for and we don’t know anything about. So, building that relationship between the phenotype, the genotype, and the broader community is a way to start to codify and identify disease entities and find other patients and families that share the same condition. There may be circumstances where there’s already a solution that’s been identified somewhere else. We would like to get access to that solution. If we end up providing diagnoses, solutions, or answers to our families, we want to share that with as many families as possible and as many investigators as possible. The other goal is that by building a really high quality database, we will attract the very best analysts to come in and work with that data, because they go to the source, they go to where the data exists in order to test out their cutting-edge analytical tools. There’s so much work to be done in that area. I would be very happy if someone else makes great discoveries using our data that ultimately benefit children and families. That to me would be a success.
Daniel Levine: Even though the program is relatively new, you’ve made quick progress. How many families have enrolled so far, how much sequencing has been performed, and what’s been the outcome?
Tom Curran: There are 2,230 families enrolled and, of that number, there are 2,600 patients enrolled. To date, we’ve sequenced 10,200–there are new genomic analyses. From that we’ve achieved 250 genetic diagnoses and we’ve contributed to the reporting of 10 new disease genes. We’ve also advanced research in families of diseases that are thought to be different, such as cerebral palsy and Down syndrome, but actually have critical genomic components. And in the case of cerebral palsy, some of the conditions turn out to be caused by genetic variants, not by specific deprivation of oxygen during development or birth. In Down syndrome we know the genetic anomaly, but what about all the other genes? Are they contributing to the range of phenotypes that you see in Down syndrome? So there are many diseases that benefit. We’ve got about 350 families with these more common diseases that are benefiting from the genomic analysis as well.
Daniel Levine: What’s the long-term expectation for the program? What impact do you expect it to have beyond the people you sequence and diagnose?
Tom Curran: The real ambition is that we want to change the face of medicine. We want to bring genomics in as a tool that physicians use in the regular course of medicine. We think every patient benefits from having that information as part of their medical record. For example, the application of pharmacogenomics, anyone who’s taking any medication could benefit from knowing if they have a gene variant that affects your ability to metabolize or absorb that particular medication. So, the longer term is that the way we develop this program may end up being a model for how adult medicine is pursued in the future. The intermediate term is working with others. We have the group that we’re working with here and we’re recruiting patients both locally and from all over, as long as they fit profile for this particular research study. We are partnering with investigators everywhere in the world. If others look at this as a model and then develop something similar or even something better, I’d be very happy that happened. We don’t own this exclusively. We want to share our approach and inspire others to do similar things, because then the database would grow and maybe multiple databases would be able to cooperate. We’re trying to work closely with the Ontario Institute. Dr. Pastinen has very good connections there to participate in their data sharing program, because they’ve pioneered some aspects of data sharing that we want to emulate.
Daniel Levine: Tom Curran, senior vice president, chief scientific officer, and executive director of the Children’s Mercy Research Institute. Tom, thanks as always.
Tom Curran: Thank you very much, Daniel. My pleasure.
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