 It's a pleasure to be here, and I've enjoyed hearing the other presentations today. So I'm going to try to be a representative from the National Institute of Child Health and Human Development, but I don't know if I'll completely succeed. We have a pretty broad mission. But I do want to at least focus on two of the programs that we're engaged in. One is looking at collaborations with NHGRI in the reproductive prenatal and neonatal genomic space, and then I want to tell you about the Include Project to study Down Syndrome, which has just been launched and was alluded to by Dr. James Coulomb in his presentation. And then finally, I had to end with something provocative to try to keep you awake, so you'll have to stay tuned for that. So first of all, collaborations in reproductive prenatal and neonatal genomics. These are sort of a challenge. Now, you know, our broad mission, and you know what, I have to say, okay, here we go, is that although we are the Child Health Institute, I have to contradict a little bit about what Chris Dawson said this morning. We actually only fund 18% of the child health research across NIH. That means the other 26 institutes and centers are funding the remaining 82%. Now, that 18% is probably the largest proportion of any of the institutes at NIH. But nonetheless, there is child health research that is really spread throughout NIH. And our mission is one that includes studying pregnancy and neonatal health, childhood health. We also have the National Center for Medical Rehabilitation Research. So we have a large portfolio in rehab medicine. And then we have research on children and on intellectual and developmental disabilities. And this is a picture of Eunice Kennedy Shriver, who in the 60s and 70s opened up her own private swimming pool to children of color with intellectual and other disabilities to swim, and was pretty groundbreaking in her own right. So that's what we're all, that's what we're trying to cover with a limited budget. When you think about selected human genomics topics that are funded by NICHD, there's a bit of a range. But none of these really is that well funded at NICHD. In the reproductive genomic space, we're only funding about $5 million in research and reproductive genomics. This is really underfunded across NIH in general. Prenatal genomics really includes the biology of pregnancy or epigenomics, and that's a little bit better funded, about $27 million. Neonatal genomics is only about $8 million, and even less for SIDS. So what we really are looking at is a dearth of research in these domains. So we have engaged in partnerships. That's what we do at NIH. When we don't have enough funding to really tackle something, we try to find other partners. And so in collaborating with our partners at NHGRI, we've been involved in the ClinGen project that you've heard about today, the Undiagnosed Diseases Network, Gabriella Miller Kids First Research Program. And then I want to introduce you to a program called the Newborn Sequencing and Genomic Medicine and Public Health, or INSITE program. So this has been co-funded by NHGRI and NICHD, and it's wrapping up its first five years. The goal is to explore the challenges and opportunities associated with the use of genomic sequencing in the newborn period, including ethical, legal, and social issues. Now you can imagine when you start talking about sequencing newborns, some people get their hackles raised. And so this has not been a project without controversy. But we also think it's very important to be systematic and thorough about how you explore this in a pilot manner so that you can actually start to make some progress and make some important discoveries. One of the goals is to compare with known newborn sequencing results. And there have been four funded awards that are now going to be completing a no-cost extension in August of 2019. These are the four funded sites. And they're really trying to answer one or more of these three questions. How can genomic sequencing replicate or augment what is known newborn biochemical screening results? Right now, newborn screening is really based on biochemical assays for the most part. So genomic sequencing has the opportunity to really augment or potentially replicate or replace conventional newborn screening. What knowledge about conditions not currently screened for newborns could genomic sequence of newborns provide? And then what additional clinical information can be derived and learned by sequencing newborns, not necessarily just newborn sequencing, but newborns for other contexts. And I wanted to highlight just a couple of the discoveries from the N-Site program thus far. One of them has actually been looking at comparing head-to-head exome sequencing versus conventional tandem spectrometry and has actually found that sequencing can augment but not really replace conventional newborn screening. But there have been a number of new genes that have been discovered and that can lead to new therapies. The baby-seek program has looked at standard of care versus next-generation sequencing for newborn screening and has found that for diagnosing rare diseases, certainly newborn next-generation sequencing is superior. I think that that is probably an obvious conclusion, but it's also been interesting to see how many parents of healthy newborns have been hesitant to sign their children up for newborn sequencing. So there are some barriers with regard to understanding and implementation. And then finally, Stephen King's more at Rady Children's Hospital has been looking at sequencing of very acutely ill newborns in the neonatal intensive care unit or NICU settings and has found that sequencing, rapid whole genome sequencing sometime with results obtained within 56 hours has actually improved diagnosis in up to 57 percent of infants and actually impacted their acute clinical management in up to 65 percent or more. And this includes interventions such as changes in medication or deciding that heroic efforts are not in the best interest of the child or the family and then referring to palliative care and even reproductive genetic counseling. So this is a pretty high yield and I think many people are wondering whether newborn sequencing in the prenatal period might also provide helpful information that can guide even the delivery of that infant and the neonatal care. I think it's a very, it's a relatively small jump to consider that prenatal sequencing for phenotypes that impact humans could also be replicated in animal models such as mice. So as a follow on to the end site program, we've been trying to decide what to do next and so a group was convened by Drs. Eric Green and Diana Bianchi, my director for NICHD and basically trying to explore these issues of genomic technologies, their implementation and ethical and social implications in the reproductive prenatal and neonatal genomic space. So we're saying we've already looked at it at least in a limited fashion in neonates, let's move it even further back. Let's challenge the LC folks as well. And so we co-hosted a workshop after about a year's worth of planning in April of 2018 and we involved many members of the community. It was interesting because we brought together people who had not typically interacted before and they helped us develop some strategies and some prioritizations of initiatives. And right now we are developing some new initiatives which I can't tell you about because they haven't been made publicly available. But the major questions for that workshop were really what current genomic technologies are ready for implementation in these three spaces in the reproductive prenatal and neonatal periods? What are the LC related issues and what are the challenges to implementing these types of genomic interventions in these aspects of human health? And we have an executive summary and a meeting report that are available online and if you Google NHGRI and ICHD and reproductive health you should be able to find it pretty readily. But I just wanted to highlight a few that I think have some relevance to your activities and the COMP and INPC initiatives. So just looking at implementation of genomics in health care one of the recommendations was to investigate and develop animal models that may inform the clinical issues across the lifespan. With regard to reproductive genomics as I mentioned our investment is so low and we really don't understand a lot about the genomic and genomic causes of reproductive outcomes and reduced fertility. We also don't understand the impact of aging and environmental impacts on reproduction and how impaired reproduction might ultimately influence the health of that adult as he or she ages. And then understanding the origin of de novo mutations and gonadomosaicism in germ cells is another area. In the prenatal genomic space we coined a new word which you all may have grown about and might say well we already know all about that. We call that embryonic lethality but we don't like to use the word embryo and fetus when talking to families and putting out public documents. Sometimes that's a little controversial. So someone has mentioned the intolerome. Those are genes that are critical to human development and in which mutations are not compatible with survival to birth as a source of gene discovery. And again I think we don't really understand embryonic or fetal phenotypes very well and understanding some of the genes that are part of the intolerome may give us some clues to help us understand these genes and their contributions. And as we just heard from Dr. Murray about 25% of your genes that you're evaluating have an embryonic lethal phenotype and even with sub viability that increases even more. So I think this is an important area that has really been understudied. And then of course we want to consider the lifespan perspective and the Barker hypothesis and really understanding how these changes in the prenatal and fetal period can predict later health and disease. And finally understanding the impact over the lifespan and the variability of phenotypes related to genomic changes. So stay tuned as we try to develop new initiatives around this space. So now I'd like to switch and talk a little bit about the Include project for Down syndrome research at NIH. And I think that everybody can recognize a person with Down syndrome. Many of you probably know individuals with Down syndrome so it's a relatively common condition. It's known to occur in about one in 600 to 700 live births in the United States. So there are about 5,300 babies born each year in this country with Down syndrome. And what's remarkable is that the lifespan for people with Down syndrome has more than doubled in the past 25 years. It used to be less than 30 and now it's between 50 and 60. So that's a remarkable improvement and change. And in part it's because of our improvements in care particularly for some of the previously life threatening comorbidities such as congenital heart defects. And this is just a graph that shows that in the 1970s cardiac surgery and infants became routine. And but initially it was not the kids with Down syndrome who got their hearts repaired. It was kids who didn't have Down syndrome. But then with screening and more interventions in the 80s and 90s, 97% of children with the atrial ventricle septal defects, which is one of the more common heart defects in Down syndrome are getting repaired. And now these kids really have superior post-op outcomes than kids who don't have Down syndrome for one type of defect. But this has really been a major sea change in leading to the increased lifespan for people with Down syndrome. So just this year, less than six months ago, in part because of some advocacy organizations that were very discouraged by the lack of NIH funding for Down syndrome. We've been hovering around 15 to $20 million a year across NIH in terms of funding support for Down syndrome. And so legislation in our FY 2018 omnibus basically directed NIH to develop a trans-NIH initiative to study Down syndrome with the aim of yielding scientific discoveries that would improve the health and neurodevelopment of people with Down syndrome as well as the general population. Because people with Down syndrome are to increase risk of developing Alzheimer's disease, leukemia, heart defects, immune system problems, autism and other conditions. In contrast, people with Down syndrome are relatively protected from many forms of cancer in most solid tumors. Rarely will adults with Down syndrome have developed prostate or breast cancer, for example. And they rarely develop heart disease or have heart attacks in spite of having other risk factors such as abnormal lipid levels and obesity and diabetes and other types of risk factors. As a consequence, we've developed an NIH initiative involving 18 institutes and centers. And we just spent $22 million in additional Down syndrome funding in this fiscal year. The Include project, of course we have our acronyms at NIH, right, we couldn't live without them. So Include stands for investigation of co-occurring conditions across the lifespan to understand Down syndrome. I realize that's a bit of a stretch, but the acronym is intentional. And in part it is because people with Down syndrome and people with intellectual disabilities in general and other forms of disabilities have been excluded from many forms of research in the past. So the first component is to conduct targeted, high-risk, high-reward basic science studies on chromosome 21 biology, to assemble large cohort of individuals with Down syndrome for comprehensive analysis and biomarker evaluation, and to include these individuals in existing and future clinical trials while building an infrastructure for clinical trials. So I wanna focus on component one because I think that has the most relevance to this audience. When we talk about targeted, high-risk, high-reward basic science studies, we really wanna include some of these topics, chromosome silencing. Have you all heard of chromosome silencing? I see a few nods. So the work of Jeannie Lawrence at the University of Massachusetts, she's basically taken the exist locus or a portion of the exist locus, put it on the extra copy of chromosome 21 to basically shut down that chromosome in a cell culture environment to really show sort of proof of principle that you could potentially turn off that extra dosage of genes in a relatively controlled manner. So that's kind of a pie-in-the-sky type of therapeutic approach, but it's a really pretty exciting basic science type of discovery. We also wanna encourage people to look at multiple genes on chromosome 21 simultaneously, not a gene-by-gene approach which has been taken in the past, and unfortunately has not been very productive or successful. We also want these basic science studies to look at the epigenetic, metabolomic, transcriptomic profiling in model organisms, and I'll show you perhaps the most used model organism in this field in just a moment, but also look at induced pluripotent stem cells and brain, organoid, tissues, systems, and other model systems, and also the development of novel model systems and potentially novel mouse models. The goal here is that component one will inform the more clinically oriented components that are also a part of the include initiative. So I have to tell you a little bit, just a little bit about the mouse models for down syndrome. There is no such thing as the perfect mouse model, as you all know, but certainly not for down syndrome either. The problem is that the genes on human chromosome 21 are really distributed across three different mouse chromosomes and that has created challenges. The most common model is the TS65DN model, which is indicated here on the left. So it has 90 genes from human chromosome 21, 90 orthologs from 21, and then the problem is it has some extra genetic material from another mouse chromosome and it's missing about 56 of the genes that are found on these other two chromosomes, 17 and 10, mouse chromosomes that are basically centenic to the human chromosome 21. And these mice are also challenging to breed, but that's really been the best model for far and some of these other models each has its flaws and its limitations. This TS65DN strain was developed at Jackson Laboratory and I mentioned where it derives its genetic material. The mice actually replicate the human phenotype in some very important ways. They have developmental delays, some learning problems, they are hyperactive, they exhibit poor growth, you can see that they're smaller than their wild type lermates. They have some craniofacial features consistent with Down syndrome, as I mentioned they have reduced fertility particularly in the males and they do develop the amyloid plaques that are characteristic for Alzheimer's disease and seen in humans with Down syndrome and with Alzheimer's disease. And you can see this little ditzel of extra genetic materials, a freely segregating extra chromosome found in the TS65DN mouse. And so we have a contract with Jackson Laboratory to make these mice available. They've been successful in really making sure that to the best of the ability they are stably breeding and breeding at maximal capacity. They've eliminated a retinal degeneration gene that was in some of the mice that had been carried on. This is my poor attempt at humor, these are three blind mice because they were before they were able to breed out the recessive retinal degeneration gene. They've developed some sperm cryopreservation methods that can allow transmission through those rare fertile males. The parent of origin studies show that males and females transmit the phenotype equally well. And then there's some additional strains that have been added to this resource at JAX to make mouse models available to the Down syndrome research community. And really why this is relevant for Include is I think we would all agree we need better models of Down syndrome but we need well phenotype models that really replicate these co-occurring conditions which is the emphasis for this initiative. And ultimately it would be ideal to have a very robust model that could be used for high throughput screening pipeline as we develop drugs and therapies for this condition. So I'm not gonna go into great detail but I just wanted to point out these were just published on the NIH website yesterday and we've indicated these are some of the 49 supplements that were funded through the Include project so this is $22 million worth of money to supplement existing grants that either had a Down syndrome focus or could add a Down syndrome focus. And some of these I think are really speaking to some of the mouse phenotypes that I know you all are interested in. And some of the models and they cover the gamut from looking at models of cardiac development, looking at cell growth proliferation, looking at immune system dysfunction. I mentioned to you the studies to look at chromosome silencing and so Dr. Lawrence is actually gonna try to turn off the extra chromosome 21 in adult mice, TS65DN mice with this extra copy of genetic material using her model system that she's developed and see if she can prevent the development of Alzheimer's-like dementia in these mice. And then Bill Mobley is actually studying a treatment to try to prevent the neurodegeneration scene in these mice as well. So the second component of Include is to assemble a large cohort for panomics and biomarker studies and I think as mentioned by Dr. Coulomb, we have just co-funded two kids first XO1 supplements to study a large cohort of individuals with Down syndrome and either congenital heart disease and or acute lymphoblastic leukemia. We're also looking at another cohort with acute myelogenic leukemia. And so those two groups will be part of our building cohort of Down syndrome individuals that have had intensive omics evaluation. We're also planning to utilize the Down syndrome registry that's been developed by NIH and is available to families with a loved one with Down syndrome and this is known as DS Connect. And basically this is a place where families can enter some basic molecular, excuse me, some basic clinical information about their loved one with Down syndrome and hear about, learn about, be connected with research projects that are of interest to them. And none of this would be possible without the affiliation of our 17 institutes and centers who are part of the Down syndrome consortium, excuse me. I think there are 14 of these and 17 various advocacy groups that are also very engaged in trying to understand Down syndrome. And the final component for the Include project is building a Down syndrome clinical trials network for inclusion of these individuals in existing and future clinical trials. And I wanted to use the example of Alzheimer's disease. So we know that because they have three copies of the beta amyloid precursor protein which is found on chromosome 21, they're at very high risk of developing dementia in their 50s and 60s. We have just been funding for the last three and a half years the Alzheimer's biomarkers consortium of Down syndrome with the National Institute on Aging which is really studying over 500 adults with Down syndrome over the age of 25 and looking serially with them over the span of five to 10 years to look for cognitive tests, brain imaging changes, genetic studies and blood markers that will help us identify those biomarkers that predict which of these individuals are at highest risk to convert to dementia in the next several years. And we think that this cohort can be a good starting point for consideration and preparation for clinical trials to test interventions for individuals with Down syndrome to prevent some of the side effects of dementia. So this shows you a graphic I mentioned to you before how pathetic our funding was for Down syndrome from 2008 to about 2016, hovering between 15 and 22 million or so and then with this year's funding we've gone up to about 58 million per year and we're hoping to continue to increase that over the next several years. We have our work cut out for us but we'll see how it goes. Now in my last few minutes I just wanted to pose a challenge. Can you all tell what this diagram is? Does anybody know? He's throwing down the gauntlet. So yeah, the internet is an amazing place. You can find all kinds of interesting graphics. So anyway, my challenge to you because I'm also representing the Intellectual Developmental Disabilities Branch at NICHD and we have some problems. We have no good therapies and drugs for intellectual disabilities. We have problems with diagnosis and with identifying genomic bases. And so I just wanted to throw this out here and see if people have some ideas for how there might be partnerships that could evolve that might be helpful in this space. So as I mentioned, I think it's really difficult to identify the etiology for intellectual developmental disabilities and autism, particularly when they occur in isolation. You know, if you have a child who comes to your genetics clinic as Kate was talking about earlier today and they have a bunch of birth defects and intellectual disability, you can sort of put those together and sometimes come up with a coherent genetic syndrome and test for that and feel like, oh, I made a diagnosis. But that doesn't happen that often. And in particular, intellectual disability oftentimes occurs by itself without a lot of other physical manifestations. We certainly don't understand the role of an environment, epigenetics, and other factors in complex IDD type phenotypes. We don't know a lot of biomarkers, target molecules, or pathways. And of course, reversing a developmental brain disorder, I mean, that almost sounds impossible, right? I don't think it's impossible, but I think we want to start with more reasonable goals and things that can be addressed in a relatively reasonable timeframe. Number one, it's hard to measure IQ, hard to measure it in a mouse for sure. And it's also hard to measure improvements in IQ in a relatively short timeframe that might be part of a clinical trial for a drug. And then the comorbid conditions for many forms of intellectual disabilities are really hard to treat. And I want to highlight behavioral and psychiatric problems because those are oftentimes occur in children with intellectual disabilities, and that can be what is really devastating for the families. So, up till now, animal models have been of limited, not no utility, but they've been of limited utility for complex human intellectual disability conditions. And I'm just gonna take a slightly different spin on what Kate Rowne told you earlier today about what happens in the clinical genetics realm and what the power of next generation sequencing has meant for the potential here. So, although I've just painted a dire picture, I think there's a lot of promise here. So, in the 70s and 80s, if you came to see me in genetics clinic, I could maybe do a chromosome study and maybe diagnose four to 5% of individuals who would come through the door. With the advent of the 80s, we developed fluorescence and situ hybridization. We could probe for specific areas that might be deleted or duplicated. Maybe that bumped us up to around 15%. With genomic microarrays in the early 2000s, we really started to see some traction and seeing diagnostic yield going up in the 20 to 25 or 30% range. And this is picking up chromosome micro deletions and micro duplications. And now, with whole exome and whole genome sequencing, we are approaching diagnostic abilities in up to 50, 60, and maybe even close to 70% of individuals. So, this is huge and it's just happened within the past decade or so. And so, we're scrambling to catch up. What this means in terms of gene discovery is that we now are looking at in total genes, this little black line here, somewhere around 600 to 700 genes that have been implicated in intellectual disabilities. But we need better screening approaches with regard to identifying those variants of uncertain significance and actually interpreting their meaning in the clinical context. And this is why, this is one example of a way in which I think people are starting to do it. It's already been mentioned to you earlier today. The matchmaker exchange and some of these wonderful tools for really crowdsourcing to connect patients, clinicians, researchers, and investigators who are doing things like you're doing. I mean, it includes the Monarch Initiative and others to really try to identify causative genes, confirm that they're causative, and then hopefully develop biomarkers and treatments. So, this is really my final slide of interest. And I just wanted to sort of throw out to you what I see as some opportunities for collaboration with the fine work that you're doing with IMPC and Comp2. So, are there opportunities to investigate and develop mouse models that can inform the clinical issues that we've discussed in reproductive health and fertility? I realize that fertility is a challenge because if you make a mouse that's infertile, it's kind of hard to propagate and study that downstream, but not impossible. And I think that there are maybe subfertility and other creative strategies that can be used to identify some of those genetic causes of reduced reproductive capability. We talked about the intolerome or embryonic lethal genes, a little bit about epigenomics, fetal programming, and neonatal phenotypes, where we really don't have a lot of information. I think there are opportunities within this new Down syndrome initiative, and I think it also provides a challenge to think about understanding the basic biology of chromosomal disorders and by extension conditions that are associated with copy number variants. So, we've all been talking about single gene changes today for the most part, but has anyone really thought about, could we model a contiguous gene deletion condition in the mouse in a way that would be meaningful and would help us understand these phenotypes? I think that genes and genomic disorders that underline developmental disabilities and autism need integrated approaches not only to confirm causation, but then to take the next step, which is to develop biomarkers that are gonna help us figure out whether an intervention is gonna be effective. And all of this requires a data sharing approach, big data, data integration, team science, and this is what you guys are good at. So, I think that the environment is right for some of these opportunities. And really, I'll just leave you with this final question. What is the best role for marine models in phenotyping and in translational medicine for intellectual disabilities and for the other conditions that I've described? So, that's all I wanted to say. I just wanna thank my colleagues in the Intellectual Developmental Disabilities Branch, my colleagues also in the Developmental Biology and Structural Variation Branch that I've been sort of temporarily working as their chief too, and all of my clinical colleagues and other colleagues in this space. So, thank you.