Scientist Stories: Lindsey Criswell, Genomics and Genetics

We're good. Okay. Rudy, are we ready for our— we'll switch over. Okay. I'm happy to do the introduction. Tell you that I am delighted to introduce Dr. Lindsay Criswell, the fairly recently appointed director of the National Institute of Arthritis and Musculoskeletal and Skin Diseases, or NIAMS. And as NIAMS director, Lindsay oversees the institute's annual budget of roughly $625 million, which supports research into the Causes, Treatment, and Prevention of Arthritis and Musculoskeletal and Skin Diseases. Now, prior to joining NIAMS in February of 2021, Dr. Criswell was the Vice Chancellor of Research at the University of California, San Francisco. She's a board-certified rheumatologist, but while she was at UCSF, she was also a professor of rheumatology and a professor of orofacial sciences at UCSF. She earned a bachelor's degree in genetics and a master's degree in public health from the University of California, Berkeley, and an MD from UCSF. She earned a doctoral— a DSC degree in genetic epidemiology from the Netherlands Institute for Health Sciences, Rotterdam, and she also completed a residency in internal medicine and, not surprisingly, a fellowship in rheumatology. Now, when Lindsay moved to NIH, as you may recall, institute directors nowadays in the modern era are not allowed to have their own research programs within the same institute. They have to go join an intramural program at another institute. And Lindsay asked to have her research group join NHGRI's intramural research program, and we were delighted to have her and have her entire research group join our genome family. So she's now an investigator within our intramural program. And her own research focuses on the genetics and epidemiology of human autoimmune diseases, particularly rheumatoid arthritis and systemic lupus erythematosus. Now, I could also say that I and others at NHGRI really enjoy having Lindsay as our friend and colleague, and I can say in particular you may want to know that she and I are the two institute directors on the 4th floor of the B wing of Building 31 on the NIH campuses, and our two office suites are at the opposite ends of a very, very, very long hallway, which has not been very crowded on that floor, But I, I know Lindsay shares my view that we're really excited about seeing more and more of each other in person and our staff seeing more and more of each other as we spend more and more time in our offices rather than teleworking. So our intramural program is thrilled to have her. I'm thrilled to have her on the floor and look forward to seeing more of her. And I'm pleased to have her here today to give an update to council about NIAMS research programs, especially those related to genetics and genomics. Lindsey, take it away, and here's the remote I'm going to hand you.

Okay. So after 2.5 years of conducting meetings and giving talks from my desk at home, it is a little bit of an adjustment to be here in person, but quite a pleasure and a very hard act to follow, Eric, with that really fantastic summary of NHGRI. And it's a pleasure to have my intramural research program in NHGRI, so thank you all for that. As Eric mentioned, I'm going to give you a very brief overview of some activities and opportunities underway at NIAMS. I'm going to keep my comments relatively brief. You've had a very long session already, so don't want to keep you too long. So let's see here. All right, so first of all, a brief overview about NIAMS. I'm not going to assume that you necessarily are familiar with our institute, so a very brief overview, and then just a few selected advances that might be of particular interest to you as genomics and genetics investigators, and then some other ongoing programs and opportunities that I'm really excited about and also that might represent some good collaborative opportunities. So the NIAMS mission is to support research on the causes, treatment, and prevention of arthritis and musculoskeletal and skin diseases. To support training in basic and clinical research to carry out this research and then to disseminate information on research progress in these areas. So quite a broad set of mission areas. The Institute was actually established in 1986, but it was previously part of the National Institute of Arthritis, Diabetes, and Digestive and Kidney Diseases, which is now NIDDK, or National Institute of Diabetes and Digestive and Kidney Diseases. And I mentioned our research focus on— our mission focusing on research, training, and providing information to the public about research progress in our mission areas and how it can be applied to improve health of the population. And in the current fiscal year, our budget was $656 million. So this slide shows a breakdown of our institute budget. Primarily in terms of the amount of support that goes out to extramural investigators relative to our intramural research program. NIH is shown there on the left, and IAMS is shown there on the right, and as you can see, we devote about the same amount of resources to our intramural research program as the average at NIH, and as I'm sure you're aware, there's quite a lot of variation around that, so we devote about 10.5% to our intermural research program. So with input from the NIAMS Advisory Council as well as the public, NIAMS developed its current strategic plan covering fiscal years 2020 to 2024, and the ultimate goal of the plan is to develop patient-centered, personalized ways to improve health outcomes in the 5 core areas of NIAMS' mission. These are listed here on the slide and include the rheumatic and autoimmune diseases, skin biology and diseases, bone biology and diseases, muscle biology and diseases, and joint biology and diseases, and orthopedics. And I want to mention also the burden of the diseases within the NIAMS portfolio. These diseases affect people of all ages, all racial and ethnic backgrounds, associated with a huge amount of of human suffering with negative effects on the economy due to healthcare costs and lost productivity. And importantly, many of them are associated with chronic pain and chronic disability, and many affect women and ethnic minority individuals, either in terms of greater risk or greater severity. So a really high impact for the group of diseases and conditions that are within our mission areas. So the current strategic plan also highlights several scientific themes that cut across all areas of our mission. And these include using new technologies to identify shared mechanisms in health and among diseases, advancing patient-centric approaches, enabling precision medicine to tailor care for each patient, and addressing the health needs of diverse populations. And these topics emerged from NIAMS listening sessions that we held with thought leaders in each of our disease and tissue-specific areas. So we've recently initiated our strategic planning process for fiscal years 2025 to 2029. Once again, the plan will focus on cross-cutting thematic research opportunities as well as bold aspirations. And of course, importantly, we're requesting feedback from interested members of the public, including researchers in academia and industry, healthcare professionals, patient advocates, professional organizations, federal agencies, and health advocacy organizations. And we really feel strongly that broad community is going to be in— is going to be essential not only to improve research in these areas, but also to ensure representation for all and to address health disparities and health equity. So if any of you are interested, I hope you will take a look at this RFI and consider submitting your own ideas or sharing this with colleagues at your institutions that might be interested in contributing to this next strategic planning process. So next, as I mentioned, I'm going to provide just a few updates about some recent scientific advances in our areas that might be of interest to your community. And one of those areas relates to the muscular dystrophies. So when the molecular and genetic defect underlying fascioscapulohumeral dystrophy, or FSHD, was discovered back in 2010, then NIH Director Francis Collins, who you all know very well, noted that the discovery belonged to the collection of the genome's greatest hits. NIAMS-supported researchers at that time showed that FSHD is caused by expression of DUX4, which is a gene that is normally silent in adults. So DUX4 causes impairment in muscle regeneration, but the story turns out to be more complicated as only a small subset of muscle fibers, roughly 5%, express DUX4 in these individuals. And it's also clear that additional mutations on other chromosomes also play a role. So researchers are continuing to look for ways to silence those 5% or less muscle fibers that are expressing DUX4 at any given time, and also working to develop gene therapies therapy approaches, which together with new imaging techniques might lead to the identification of new targets for the affected muscles. So another scientific advance that I wanted to share with you, maybe some of you are aware of this, it stemmed from a very important collaboration between NINDS and HDRI, and it related to an adult-onset inflammatory disease. So, this new recognition of this syndrome, which is being called the VEXAS syndrome, for vacuoles, E1 enzyme, X-linked, autoinflammatory, and somatic, was identified in 2020, as I mentioned, by NIAMS and NHGRI scientists. And they were working with an international team that were studying an unusual group of patients that had been identified worldwide. So, middle-aged men with this condition, as I mentioned, now called called vexus were experiencing high fevers, low blood cell counts, and inflammation of the skin, lungs, cartilage, and blood vessels. They didn't respond well to therapy, and they were at increased risk of early death. So the scientists used the genome-first approach and found that the disorder was caused by a mutation in the UBA1 gene on the X chromosome. And further studies revealed, interestingly, that some patients who were previously diagnosed with a condition called relapsing polychondritis also carry this VEXAS genetic signature. So, a really important observation that helped explain some of the heterogeneity of this group of vasculitides. And excitingly, there's a clinical trial that's now underway at the NIH to evaluate stem cell transplant as a possible treatment for patients with VEXAS. I want to mention another collaboration between NIMH and NHGRI. And this one focuses on a condition known as scleroderma, which is a devastating condition that is characterized by fibrosis in the skin and also other organs associated with tremendous disability and early death in many patients. Now, recognizing that African Americans have an increased prevalence and severity of scleroderma compared to whites, Dr. Dan Kastner, who I think probably many of you know, and one of his trainees at the time, Praveet Gore, who's now in the intramural research program at NIAMS, established a consortium called GRASP, for the Genetic Research in African American Scleroderma Patients Consortium, with a goal of enrolling a large cohort of very well-characterized African American scleroderma patients to identify, among other things, ancestry-specific variants that might be contributing to increased disease risk and severity in this population. The effort now involves extramural researchers at 25 centers around the United States and has been very successful and is, I think, a fabulous example of a collaboration. And I wanted to especially acknowledge Dan Kastner's role in this. Not only did he really develop this idea and provide the initial funding, but he contributed very importantly to NIAMS as its clinical director. So And I'm also grateful to Dan, to all that he did to help me in my move to the NIH and establishing my lab at NHGRI. So I also wanted to mention that Dr. Charles Rotimi, current ASHG president and scientific director at NHGRI, also provided clinically important resources for this effort, including a biospecimen collection of African American control individuals. So thank you very much to NHGRI for your contributions in both of these and many other efforts. So sticking with the theme of collaboration, I'd like to highlight another research effort that involves collaboration and really, I think, is a fantastic example of team science at its best. And this has been critically important in allowing the advancement of understanding of a variety of diseases. And this is the Accelerating Medicines Partnership. Perhaps some of you are aware, and I'm sorry if you're all very well aware, but it was an effort that I wanted to touch upon because I think it's so important and NIAMS views this as such a high priority. So the Foundation for the NIH launched the initial AMP program in 2014, and this public-private partnership involves 15 institutes and centers, 28 industry partners now, and 29 nonprofit organizations to tackle important health conditions. And I'm sorry, the font is a little bit small, but you can probably see some of the conditions that were either part of the initial AMP back in 2014 with Alzheimer's, type 2 diabetes, rheumatoid arthritis, and lupus, and some of the other conditions that have been added along the way: Parkinson's disease, schizophrenia, etc. So these projects have been focusing on identifying disease mechanisms, biomarkers of disease progression, and hopefully potential targets for intervention. And genomics has been a very prominent theme of many of these efforts, including the ones that NIAMS has been involved in, the effort on rheumatoid arthritis and lupus. So RA and lupus were included in the initial set of AMP programs and was very, very successful. And in part, building upon that success, the FNIH has recently launched the next iteration of this, which we're calling AMP AIM, and the AIM stands for autoimmune and immune-mediated diseases. So we're very excited to be now in this next iteration of the program where we've extended the effort to some other autoimmune diseases, and I'll mention those in just a minute here. So the goal of AMP AIM is to index and map cells and pathways in psoriasis and psoriatic arthritis, Sjögren's disease, as well as rheumatoid arthritis and lupus. And the project seeks to discover how these pathways and cells interact, applying, importantly, new analytics approaches across these diseases to identify specific and shared disease mechanisms. We know that there are many shared mechanisms across this very diverse group of disorders from even the initial GWAS studies back, you know, many, many years ago. So that's been a common theme of research in this area and something that we're still trying to understand better. But NIAMS is also involved in another AMP program, the Bespoke Gene Therapy Consortium. I can't recall whether Eric touched upon this, but you've probably heard about this effort as well. And this consortium was created to speed the development and delivery of customized or bespoke gene therapies to treat people affected by rare diseases. And this BGTC is the first AMP initiative, importantly, that focuses on rare diseases. The program aims to generate a streamlined clinical and regulatory framework for gene therapy, and it's focused on 4 areas to overcome major obstacles related to developing gene therapies. These include the areas of basic research, clinical research, manufacturing and production, and regulatory requirements. And through the result of an extensive progress that completed a month or so ago, 14 candidate diseases have been selected to be the initial focus. And this list includes 2 orthopedic conditions that are listed there at the bottom of the slide, fibrodysplasia ossificans progressiva, and mucopolysaccharidosis 4A. So really, we're very excited that there's an opportunity for some of the NIAMS diseases and conditions to be included in some of the initial studies of this new consortium. So the NIH and AMP and other AMP partners are continually considering how to maximize the impact of this program and these programs to accelerate the development of new therapies. So, recently, the AMP Executive Committee approved a new concept that will focus on inflammation as a theme and use a systems biology approach. So, the goal is to create an integrated research ecosystem—that's something that Eric was alluding to in his comments—and a systems biology model for understanding chronic diseases generally. And shown on this slide are some of the elements of a systems biology approach, and data collection and generation and analysis in many of these areas is already underway with— across many of the AMP programs. So there's a major opportunity here. So there are now 11 industry partners that are interested in participating, and the NIH is gauging interest among the ICs, and I certainly hope that NHGRI is going to embrace this this opportunity, a new AMP program. So we expect the development of the project plan to begin in the next few months. And importantly, these programs have significance for how research could be enhanced beyond the specific diseases being studied to leverage ongoing efforts in related activities as part of a research ecosystem. Recently, Dr. Larry Tabak, who's performing the duties of the NIH director while the search for a permanent director continues, he transferred transferred responsibility for the Regenerative Medicine Innovation Project, or RMIP, from the NHLBI to NIAMS, and this was at the suggestion and request of NHLBI, so this was a very friendly transfer. So this NIH-wide project aims to accelerate progress in the field by supporting clinical research on adult stem cells, while at the same time promoting scientific rigor and protecting patient safety. So we're pleased to have this opportunity that recognizes the fact that regenerative medicine is a priority for the NIAMS. Now, along those lines, NIAMS is also hosting a roundtable on cartilage preservation and restoration in knee osteoarthritis, which aims to identify challenges, gaps, and opportunities related to regenerative medicine for this very common condition. And this videocast is This roundtable is occurring just later this week and will be videocast, and I hope that those of you that might be interested will tune in. So the stakeholders, which include investigators with expertise in regenerative medicine, experts in clinical treatment of NEOA, and FDA representatives, will be discussing where and how NIAMS can play an important accelerating role in this really exciting area. So, of course, one of the important and emerging opportunities for team science programs like the AMP is data management and sharing. Eric already referenced the new NIH Data Sharing Policy, and we're excited that that can build upon existing genomics data sharing policy— the policy— and also improve the availability of data and provide further opportunity to study the genetic and genomic contribution to many diseases within the NIAMS mission. But we're also thinking about how team science projects like the AMP can provide opportunities for collaboration and workforce training in the area of data science. So along those lines, NIAMS is partnering with the Office of Research in Women's Health on a Team Science Leadership Scholars Pilot Program. The scholars will be embedded in the AMP AIM network, which provides the ideal environment where investigators can develop skills both conducting and managing team science so that so that they can themselves become leaders and mentors for future generations of scientists. This is a brand-new program. We plan to support 3 or 4 of these embedded scholars and to support them in this pilot phase for 2 to 3 years. But we hope to expand this program beyond these initial scholars that will be embedded within AMP, and the Office of Data Science and Strategy is really excited about helping us extend this effort. Now, NIAMS has also recently launched a data science strategy working group in collaboration with our council, which is part of our overall data science strategic initiative. So I wanted to tell you a little bit about that. I thought might be of interest. So we're thinking about this as a two-prong strategy to understand the needs of both our extramural community as well as our intramural research investigators, and how to leverage existing and planned efforts to provide resources for the community. There's a lot of activity in this area, and we want to leverage all of those plans' effort, and it's hard, frankly, even to keep track of what's happening in this space. So, this graphic shows the variety of inputs that will inform the creation of a NIAMS data science strategic plan, and as I just briefly mentioned, We've convened a working group of our advisory council to bring the perspective of the extramural research community, but we've also assembled an internal group to plan how to develop a set of actions and to implement solutions. So our strategy will address the needs of investigators, criteria for high-value data sets, requirements for data infrastructure, safety, and operability, and it will also allow us to consider the scientific opportunities the state of the workforce, and approaches to foster a culture of data sharing, which is also critically important to success here. So the goal is to provide new guidance, resources, tools, training, and standardized criteria to enable robust data sharing and management. So a lofty goal, but really important. And this slide just focuses in on that working group of our council that was recently created, and this group is charged to provide general guidance to NIAMS on opportunities in data science big data and bioinformatics relevant to our mission areas. And I've listed some of the areas of recommendations that we hope our working group will consider. I've mentioned investigators' need, including what they need to meet these new data sharing and management policies, what role NINDS can play in fostering a culture of data sharing, data infrastructure and interoperability needs, and security, criteria for high-value datasets, artificial intelligence and machine learning scientific opportunities, and how we can leverage lessons learned from the NIH and other community resources. So on that note, I just want to say, for those of you that might be interested in reading a little bit more about NIAMS or some of our funding opportunities, please check out our website. You can also find us on Facebook and YouTube, and we also publish our funding opportunity announcements and our notices of special interest through a funding newsletter that you can sign up for and at the NIAMS funding Twitter account. So on that note, I'm happy to take any questions. Well, thank you, Lindsay.

Actually, let me jump in and make two comments, and then I really want to put the floor open to council members in particular. So two things you said I thought were interesting. First of all, we are indeed— NHGRI, as you mentioned, is participating in this new bespoke gene therapy program. I'm not sure we've ever told council about it because we've mostly just— it's more of a promissory note. We're going to give funds for it, and, and, but, but yeah, looking at Terry, maybe we could add it to a list of a future director's report slide so we could tell them a little bit about it because we are definitely going to be providing, uh, some funds for it. So we have signed on to that and believe this is very valuable. I'm glad you highlighted some of this for council. Second thought is this last thing about I think it's interesting that you also have a data science working group of your council that you're just starting. And we've had one— I'm looking around— how many years? About 4 or 5 years, you think? We found things about 5 years. So we have one that's been well established, a couple members up here on the council that serve on that working group. And then we have some ad hoc members also serving that. And that's a very active group. And I'm just making the observation, and maybe at some point, or maybe Valentina or somebody could compare notes of the topics they're covering or things they're going to talk about. Maybe it's not a crazy idea to have a joint meeting or something at some point and bring those two working groups together, because I just don't know how many other— I guess I could ask. I just don't know how many other institutes, councils have working groups in that area. We were very proactive. You obviously agree with this idea, and maybe getting some interactions might be worthwhile. And even if nothing else, start by maybe sharing your roster, and we could share our roster. We could look at the people who are community, you know, because Some of the challenges are going to be unique to your, your research and maybe unique to ours, but I bet a lot of the challenges are going to be quite common.

I'm sure there's going to be a lot of common ground, and I'm sure we can learn a lot from you. So thank you very much for, for raising that, and that would— that's a fantastic idea. And step one is we can share our roster.

Yeah, so maybe is there a single program director you have who runs that working group?

Susanna Stein is the best initial contact, and I can share that.

Okay, you could just share that with me or Valentina if you know that person. Well, I think we should connect and make sure those groups are at least aware of each other because I think it's a terrific opportunity. Okay, council members, questions? So we've got Nancy with her hand up. Okay, Nancy.

Dr. Criswell, that was fantastic. I really appreciated that overview, and I'm really glad to hear about the GRASP program. GRASP, um, I think that that's a, it's a great initiative, and I'll be anxious to see what they turn up. But I was also— you guys are clearly all over the concept of shared genetic architecture, both with this concept around the inflammatory biology contributing to multiple diseases. But of course, working in the autoimmune space, you can't escape the shared genetic architecture across those diseases. And what you guys are accomplishing is kind of a model for what needs to be done in some other spaces. There was a lot of discussion of this at the recent World Congress of Psychiatric Genomics, where there's clearly a lot of shared genetic architecture. It's a little harder to understand the biological basis for the shared genetic architecture, although there are some emerging things. But I think there's a great opportunity to contribute to this larger space. That you guys are already so invested in. And I'd love to hear more from you on how you plan to sort of get this roadmap out to the rest of NIH.

Yeah, thank you very much. And I see Howard Chang on the board there, too, and he's very familiar with opportunities in scleroderma. So you mentioned GRASP, and there, what we're trying to understand— and this is true for many diseases, systemic lupus is another example— is, What is it? Is it, you know, simply genetic ancestry? Is it history? Is it environment? Is it gene-environment interaction? What is it that explains this variation in disease risk? And we don't have great data from populations around the world to be able to fully understand this. So I really applaud this effort by GRASP. It was challenging to get all of these 25 institutions together, which is what you need to identify and develop a cohort that is appropriate to actually advance knowledge in this area. So I really applaud the GRASP effort, and NHGRI gets a lot of credit for that. But you may also be referring back to the Accelerating Medicines Partnership Systems Biology of Inflammation, which, you know, is— it really is conceptually conceptualizing that issue much more broadly. And it grew in part out of some initial observations in the Accelerating Medicines Partnership where discoveries that were being made specific to rheumatoid arthritis, say it's synovial cells or kidney cells in lupus, overlap with findings in Alzheimer's or Parkinson's disease. So brand new connections that we hadn't been conceiving of, and we recognized that, wow, we really need to be designing our efforts so that we can maximally leverage what we're doing across all of these, this broad range of disease spaces. And unfortunately, Back in 2014, that— there wasn't perhaps sufficient effort on how to develop these independent projects in such a way that the data would be interoperable, common data elements, et cetera, et cetera. But a huge amount of effort is going into that now with the launch of these other efforts. So I'm really excited at the prospect of developing and evolving this effort in such a way that we can much more quickly identify connections between diseases that we didn't appreciate. And it reminds me a little bit of drug repurposing. You know, and efforts that say— and there was a rheumatoid arthritis study a number of years ago that was really interesting. They took all of the GWAS hits, and they mapped it onto pharmaceutical pathways. And you immediately saw, wow, there are these cancer drugs that should be good targets, at least for intervention in rheumatoid arthritis. And we would never have gotten there had we just one at a time started testing drugs in rheumatoid arthritis. There's shared genetics. There's things we don't understand about common and distinct features. What is the role of the environment? And we're thinking we're limited by the way that we've defined these diseases, our classification criteria. So we're not thinking about potential overlap with diseases outside of those, you know, those frameworks. So thanks for your enthusiasm. I hope that we can really encourage other efforts across the NIH to to move forward in a similar way.

I see Michael Chang's hands up. Howard. Yeah, I know a Michael Chang. Howard Chang.

Dr. Kressler, that was a fantastic presentation. Thank you so much. Can you please say more about the data science management and training program? How is that going to be— how's that going to be implemented, and what are the sort of the criteria for success? And training future leaders?

I'm not sure whether you're talking about this new scholars pilot program that we're just initiating now. That's correct. Yeah, right. So, so this is brand new. In fact, I just announced this at our council meeting a few days ago. And some important things. First of all, we do not want this opportunity to be restricted to those who are already participating in the AMP network. Very, very important for us. That presents a challenge. How do we get the word out? And this is one way that we can get the word out is by sharing this with other councils, so it will be open to anyone. We're going to leverage the CTSA networks across the country. We're going to collaborate with all of our communication, the teams across the NIH. There's a program called Building Interdisciplinary Careers in Women's Research, the BIRCWH network, that we're going to be getting the word out, and of course, the AMP investigators will be getting the word out as well, and as I mentioned, 3 or 4 scholars will be chosen. They will then be embedded in AMP, and we'll support them for 2 to 3 years, but really good question. How are we going to evaluate the success? To be perfectly honest, we haven't gotten that far, and I think that's a really important a really important comment in terms of, first of all, is it successful? If so, how is it successful? Where is it not meeting the needs of the community, etc.? The other thing I want to mention is that it's intended to be open to folks who might want an industry experience or folks from industry who might, you know, be interested in an opportunity to be embedded within the network. So we're starting it off. We're starting it off really small, just within AMP, but You know, hope that— and, and we haven't even had a chance yet to speak to Susan Grigorek, who's the director of the Office of Data Science Strategy. She just heard about this last week and said, we're really excited to partner with you and extend this program in other areas. So stay tuned for more information on that front.

Mark, thank you for your presentation, Dr. Criswell. So I'm curious what the thinking at NIAMS is about the the need for or plans to develop a cloud-based data commons to support your mission? Are you thinking about developing your own or piggybacking on Anvil and BioData Catalyst and the others or doing something else?

Yeah, so in fact, last Friday, as part of our strategy meeting, we had Alistair— shoot, I'm blanking on his name— the Alistair Stevens, I think it is, the BioData Catalyst director present, and we were so impressed. And we definitely, as a small institute, we're not the data science institute, although we recognize it's, it's important. So we have to leverage efforts that, that exist, that are being built, that, that will be built. And, um, you know, right now what we have is we have very important resources that we're supporting in different ways. Within our internal research program and our external research program, and we don't have a kind of a common plan or a holistic comprehensive plan for that. I will say, though, that one of the advantages of conducting research within AMP is we can leverage some of the resources that are being developed. For example, we plan to leverage the Accelerating Medicines partner NIA investment the Sage Bionetworks resource, we can leverage that for some of our data sharing and storage. But, you know, it still feels like kind of cobbling together resources and information. And— but we do not think that, you know, we're hoping not to have to build something on our own, but rather leverage relevant existing resources in an efficient way. Judy?

Yeah, to follow up on the strands of repurposing shared pathways, gastroenterologists aren't as smart as rheumatologists. So, the next new drug is always whatever's been used in rheumatoid arthritis for Crohn's disease. But, you know, what's going to happen in terms of GWAS signals in the single-cell era, you're going to see enrichment of cell-specific enhancers. So, that's all going to happen inevitably in the next 5 years. The challenge as I see it is in combo therapy a little bit. Serial sampling in the context of interventions. Have you been able to do that in AMP? Because I really see that as critical to logically and rationally designing combination therapy protocols.

Yeah, so as you can imagine, it's been difficult to, you know, develop the pipeline in terms of appropriate samples that can answer all of these questions. You know, patients that are naive to therapy and are going on a particular drug for the same time, or the before-after initiation of a drug. I think that the looking specifically at specific therapies is going to be a greater focus in this current iteration of the Accelerating Medicines Partnership program for autoimmune and immune-mediated diseases. But— and off the top of my head, I can't recall exactly what the different subgroups were. But it was a challenge because we were also trying to get target tissue in these diseases. We were getting synovial tissue in rheumatoid arthritis, which in addition to PBMCs. We were getting kidney and skin tissue in lupus in addition to peripheral blood mononuclear cells. So, so first of all, we had to figure out how to get the synovial samples in an efficient way. That was a couple of years. And then how to implement this across these sites in a standardized way, how to process the tissue tissues in a uniform way to support single-cell approaches, etc. You know, the pipeline for analyzing all these data, the different, etc., etc. So it's been a big challenge, but definitely high on the priority list is understanding what's happening in the naive state. In fact, I think one of the common projects that is common across all of the 5 autoimmune conditions in the current AMP program is going to be early-stage disease. So early disease before anything's happened. You know, so let's have a common pipeline across, you know, all of these conditions and try to understand what's happening before, you know, sometimes before a definite diagnosis, and certainly before treatment. So challenging though. But that's the goal, as well as kind of sample collection before and after treatments are initiated.

Any last questions for Lindsay? I'm just— what do you see? Oh, I'm sorry. I didn't see.

Since inflammation and immunity are dysregulated in so many organ systems, how do you advise investigators that are applying where the areas are overlapping? For example, cardiovascular and immunity or inflammatory dysregulation, or even NHGRI and NIMH can overlap. I mean, when we talk to Eric, he says, you know, we have 4 institutes, so go apply somewhere else in terms of when there's an overlap. What is your philosophy towards that kind of an issue?

The goal is to fund the best science across the country. So if that means that an investigator, you know, who we view as part of our community is best able to secure some funding through NHLBI or NIAID, you know, go for it. You know, if, if If there's science that falls between two institutes and if the other institute says, "We can't fund that mechanism. This is not one of our priority areas, but if we think it's important, we will do our best to fund it." I wish there was more co-funding, but that's another thing that we do with other institutes. So one of the challenges we have is that we receive a very, very large number of applications relative to our budget. We're a small institute with a broad mission and a smallish budget, so we can't fund everything that we'd like to fund, so that's a challenge right at the outset, so we have to leverage other funding opportunities for our investigators. Sometimes that means NIAID has this great program. Hey, make sure you don't miss out on that, or maybe it's the Common Fund. Maybe ARPA-H will be a way to get some really important science done that we're not able to fund, et cetera. So we need to make sure we're spending our money in the best possible way, leverage other resources, partner. We have lots of examples of partnerships with other institutes. One of my personal goals is to have some sort of a collaboration with every single institute. So we're getting there. Partnering is great, especially certain institutes that might have lots of resources in a particular area where we're under-resourced. So it's a little bit case by case, but the goal is to make sure that the best science gets funded somehow. Sometimes it falls to professional organizations. Sometimes they can really make a big difference— bridge awards for early-stage investigators, for example. Or lupus is an area where there have been fantastic scientific organizations that have really stepped up to the plate and fund a lot of lupus research. More than we can fund, which is great.

Lindsay, thank you very much. That was really terrific. We clearly identified a number of things I didn't even know about that are really important for us to think about, and I'm sure this gave our council members ideas for potential future interactions.

Thank you so much, Eric. Yeah, nice to meet you all. Thank you, Lindsay.

Okay, take a mask. Yeah, you're gonna be muffled. Oh yeah, you've earned lunch. So I believe for the council members it's been delivered outside. So let's reconvene at 1 o'clock.