NIH Director Research Articles

The origins of ADNI.

A brief history of events surrounding the conceptualization and original implementation of the Alzheimer's Disease Neuroimaging Initiative (ADNI) as a public-private partnership (PPP) is provided from the perspective of three individuals directly involved from the outset. Potential barriers and how they were addressed are summarized, especially the decision to make all data freely accessible in real-time. Decisions made at the beginning of ADNI are revisited in light of what has been learned over the past 20 years, especially the importance of the investment in cerebrospinal fluid (CSF) and blood measures and the commitment to data sharing. The key elements of ADNI's success from the authors' perspective are also summarized. HIGHLIGHTS: Informal interactions among colleagues were the beginning of something big. An NIH Director's personal decision on open data sharing has had perhaps the greatest impact of any single decision in the past several decades in terms of advancing clinical biomarker research. After 20 years, blood-based biomarkers of brain disease may soon take the place of brain imaging for purposes of diagnosis and drug development.

The division of rare diseases research innovation at the national center for advancing translational sciences, NIH: mission, history, and current research activities

The mission of the NCATS Division of Rare Diseases Research Innovation (DRDRI), formerly known as the Office of Rare Diseases Research, is to advance rare diseases research to benefit patients. DRDRI is part of the National Center for Advancing Translational Sciences, one of the 27 components of the US National Institutes of Health. DRDRI facilitates and coordinates NIH-wide activities involving rare diseases research, as well as directly supporting rare diseases research activities. These activities include the development and maintenance of a centralized database on rare diseases; collaboration and coordination with organizations focused on orphan products development and rare diseases research across the globe, advising the Office of the NIH Director on matters related to NIH-sponsored research involving rare diseases; and responding to information and policy requests about rare diseases within the NIH. DRDRI also supports various rare diseases research activities, including the Rare Diseases Clinical Research Network, rare disease-related conference grants, and assessment of the costs of untreated rare diseases. In addition, several of the projects DRDRI is supporting are “many diseases at a time” translational approaches for rare diseases, which emphasize leveraging commonalities across multiple rare diseases. These include the support of “basket trials” based on shared molecular etiologies across multiple rare diseases, as well as therapeutic platforms for the treatment of monogenic diseases, such as gene therapy and genome editing. This Perspective will provide an overview and summary of these various activities, noting where relevant our collaborative partnerships within the U.S. and internationally.

Transitions in development - an interview with Berna Sozen.

Berna Sozen is an Assistant Professor in the Department of Genetics at Yale University, USA. Berna's lab studies early mammalian development, metabolism, and maternal-fetal interactions using mouse and human embryos, as well as stem cell-derived embryo-like models. In 2022, Berna received the NIH Director's New Innovator Award. We spoke to Berna over Zoom to learn more about her journey to becoming a group leader and the importance of making science careers accessible.

SENNET CONSORTIUM: OPPORTUNITIES AND CHALLENGES

Abstract The Cellular Senescence Network (SenNet) Program was established in 2021 by the NIH Director’s Office Common Fund with the goal of comprehensively identifying and characterizing senescent cells across human lifespan in numerous organs. Mapping senescent cells in mice was added in 2022 to leverage genetic and pharmacologic approaches to drive, report, and ablate senescence in vivo. Senescent cells are implicated in driving most if not all age-related chronic diseases as well as accelerated aging caused by chronic diseases and their treatments (e.g., cancer chemotherapy). Furthermore, therapeutics specifically targeting senescent cells (senotherapeutics) have been developed and are currently being tested in clinical trials for multiple disease and geriatric endpoints. Thus, identifying and characterizing senescent cells throughout human aging and disease states has the potential to significantly impact human health. The SenNet Consortium is a highly collaborative network of scientists across the globe jointly benchmarking tools, technologies, and data analytic approaches, and aligning their activities with other NIH Common Fund initiatives, such as HuBMAP. While mapping senescent cells holds great biomedical promise, there are challenges such as the absence of specific biomarker to identify senescent cells, the appearance of senescence under physiological and pathological conditions, and little knowledge of what drives senescence in vivo. Analogous to the Human Genome Project, to achieve SenNet goals, innovative tools and technologies for single cell and spatial tissue analysis must be developed. Products of SenNet, in addition these new approaches, will include common nomenclature to define senescent cells, novel biomarkers of senescent cells, and publicly accessible databases and 4D atlases of senescent cells in 18 human and murine organs that enables 4D visualization.

Biden nominates Monica Bertagnolli to lead NIH

President Joe Biden has nominated Monica Bertagnolli to be director of the US National Institutes of Health. If confirmed by the Senate, Bertagnolli would be the second woman to lead the NIH since the agency was founded in 1887. The first was Bernadine Healy, who was appointed in 1991. Last August, Biden appointed Bertagnolli, a cancer surgeon , to direct the NIH’s National Cancer Institute (NCI). She was the first woman to hold the position. “Dr. Bertagnolli is a world-class physician-scientist whose vision and leadership will ensure NIH continues to be an engine of innovation to improve the health of the American people,” Biden says in a statement announcing the nomination. Bertagnolli will be filling a position that opened up when former NIH director Francis Collins stepped down in December 2021. Lawrence Tabak has served as acting director. Before her appointment to the NCI, Bertagnolli was a professor of surgical

Four challenges facing Biden’s nominee for NIH director

Four challenges facing Biden’s nominee for NIH director

Long-term metabolomic alterations during post-acute sequelae of COVID-19

Abstract A large fraction of COVID-19 patients does not fully recover from the acute infection with SARS-CoV-2 but develops long-term symptoms that persist for several months. The pathobiology of such post-acute sequelae of COVID-19 (PASC, “long COVID”) remains largely enigmatic. This project is based on a discovery made by a plasma metabolomics exploration of individuals with acute SARS-CoV-2 infection, post-COVID patients that have fully recovered from the disease, and PASC patients that have persistent manifestations across a wide range of organ systems. We have found key metabolites that are altered by acute SARS-CoV-2 infection and do not recover in individuals with PASC, while returning to normal levels in post-COVID individuals who do not develop long-term symptoms. These metabolites offer a pathway-level hypothesis for a new molecular etiology underlying PASC. We have shown that viral RNA is sufficient to alter these metabolites and suggest that this can explain some of the symptoms reported by patients with long covid. A.C.W. is supported by training grant T32-AI-055400-19. C.T. is a Pew biomedical scholar and a Kathryn W. Davis Aging Brain scholar and is supported by the NIH Director’s New Innovator Award (DP2-AG-067492), the Agilent Early Career Professor Award, and grants from the Edward Mallinckrodt Jr Foundation, the IDSA Foundation, the Thyssen Foundation, PennCHOP Microbiome Program, Penn Institute for Immunology, Penn Center for Molecular Studies in Digestive and Liver Diseases (P30-DK-050306), Penn Skin Biology and Diseases Resource-based Center (P30-AR-069589), Penn Diabetes Research Center (P30-DK-019525), Penn Institute on Aging and the Borrelli Family Pilot Grant in Lynch Syndrome. M.L. is supported by the NIH Director’s New Innovator Award (DP2-AG-067511), an American Cancer Society Scholar Award, The Pew Scholar Award, the Searle Scholar program, the Edward Mallinckrodt Jr Foundation and grants from the Abramson Cancer Center, The Penn-CHOP microbiome program, Penn Coronavirus Center Pilot, Penn Institute for Immunology, Penn Center for Molecular Studies in Digestive and Liver Diseases, Penn Center for Precision Medicine, Penn Institute on Aging, Penn Center of Excellence in Environmental Toxicology (P30-ES-013508) and the Borrelli Family Pilot Grant in Lynch Syndrome.

Behavioral Medicine Research Council (BMRC) Statement Papers: A New Approach to Consensus Building in Behavioral Medicine Science.

In his departing remarks, outgoing NIH Director Dr. Francis Collins lamented that he should have engaged more with behavioral science to develop COVID-19 mitigation strategies [1]. Behavioral medicine can contribute unique value to public health efforts to achieve optimal health for all. Yet, we continue to see gaps in the dissemination of behavioral medicine research and gaps in the effective translation of science into public health practice and policy. The Behavioral Medicine Research Council (BMRC) ­addresses these gaps by building a strong collaborative foundation for behavioral medicine. The BMRC is an autonomous, joint committee made up of representatives from the four leading U.S.-based behavioral medicine organizations: the Academy of Behavioral Medicine Research (ABMR); the American Psychosomatic Society (APS); the Society of Behavioral Medicine (SBM); and the Society for Health Psychology (SfHP) [2]. The goal of the BMRC is to identify strategic behavioral medicine research goals and promote systematic, interdisciplinary approaches to achieve them. The efforts of the BMRC include but are not limited to identifying specific research targets, prescribing best practices, cultivating a field-level culture, and building coalitions and joint advocacy to improve the influence of behavioral science in the broader research community, and the public, and policymakers. The BMRC comprises two distinguished senior scientists to represent each of the member societies for 3-year terms. In addition, the editors-in-chief of the three major journals—Annals of Behavioral Medicine, Health Psychology, and Psychosomatic Medicine—also engage in coordinating and facilitating dissemination. This coalition represents a new effort to harness the field’s collective strength and lead toward a more remarkable impact on population health assertively.

Recent trends of “manels” and gender representation among panelists at the ASCO annual meeting.

11053 Background: Gender disparities in academic medicine are a long-acknowledged concern. Efforts to recognize this imbalance and increase inclusivity continue, particularly in academic medical conferences. In June 2019, NIH Director Francis S. Collins MD, PhD publicly called for an end to all-male speaking panels (“manels”). It is unclear whether academic oncology conferences followed suit. We investigated the prevalence and longitudinal trends of manels and gender representation at the ASCO Annual Meeting during 2018-2021. Methods: Using ASCO online programs, 2018-2021 faculty information was obtained. Data collected included perceived or self-reported gender, medical specialty, panel role (chair vs. non-chair), type of session, and topic. Primary outcomes included percentage of manels and proportion of female panelists over time. Female representation among chairs, specialties, and topics were evaluated. Cochran-Armitage test was used to analyze time trends in the proportion of manels and female representation. Fisher’s exact test was used to compare each session type, topic, or specialty to other categories combined. P-values are based on a two-sided hypothesis. Results: During 2018-2021, there were 670 sessions total, 81 of which (12.1%) were manels. Among 2,475 faculty members, 1,181 (47.7%) were females. Over time, there was a significant decrease in the number of manels, from 17.4% in 2018 to 9.9% in 2021 (p = 0.030) and a corresponding increase in proportion of female panelists from 41.6% to 54.0% (p < 0.001). The largest decrease in manels occurred between 2018 (17.4%) and 2019 (10.5%). Among session type and topic, the highest proportion of manels was observed for leadership/special sessions (17.1%, p = 0.419) and translational/pre-clinical topics (19.6%, p = 0.024), respectively. The chair role was majority male (53.2%) in 2018 but increased to > 50% female representation in 2019-2021 (p = 0.157). The lowest proportion of female panelists were in pathology/radiology/dermatology specialties (combined 26.2%, p = 0.001). Female panelists were underrepresented for the topics of genitourinary cancers (38.6%, p = 0.029) and translational/pre-clinical sciences (36.7%, p < 0.001). Females were overrepresented in the topic of supportive oncology (70.3%, p < 0.001). There was a positive trend toward improved female representation among translational/pre-clinical sciences (27.4% in 2018 to 41.8% in 2021, p = 0.031), but with little improvement among genitourinary cancers (41.1% in 2018 to 40.7% in 2021, p = 0.969). Conclusions: The number of female ASCO panelists increased during the study period and surpassed 50% in 2021, with a corresponding decrease in the proportion of manels. Still, there are certain topics/specialties where female representation has remained stagnant. ASCO Annual Meeting organizers should continue to strive for diverse gender representation and the elimination of manels.

C&EN talks with Francis Collins

As he prepared to step down as director of the US National Institutes of Health, Francis Collins was feted by some of the US’s highest-profile politicians, scientists , and musicians. A farewell video produced by the NIH included send-offs from four US presidents, dozens of scientists, and a multitude of other famous figures he’d encountered during his tenure at the NIH, such as comedian Stephen Colbert, musicians Yo-Yo Ma and Barbra Streisand, and historian Henry Louis Gates Jr. “It was astounding,” Collins told C&EN Dec. 17, 2021. But while it’s nice to be recognized, Collins’s real legacy will be in the status of the agency he led for 12 years. That is the longest tenure of any NIH director since the position became presidentially appointed in 1971 . The NIH consists of 27 institutes and centers that support health research. It employs scientists inside the agency and funds scientists at

Francis Collins: Reflections on being the NIH Director

For over 12 years, spanning three administrations, Dr. Francis Collins has served as the director of the National Institutes of Health. During that time, he and the NIH launched ambitious programs to spur research in diverse topic areas, with important successes. He has also confronted issues facing science and scientists. Dr. Collins recently stepped down as director. Before his departure, he had a conversation with John Pham, reflecting on his time leading the NIH and sharing his perspectives and his hopes for the NIH and the scientific community moving forward.

Lawrence Tabak named acting head of the NIH

Lawrence Tabak has been named acting director of the US National Institutes of Health. Tabak took over Dec. 20 from Francis Collins , who retired as director after holding the position for over 12 years. The NIH director is nominated by the US president and confirmed by the Senate. Tabak has been principal deputy director of the agency since 2010 and serves as its deputy ethics counselor. He was head of the National Institute of Dental and Craniofacial Research from 2000 to 2010. “Dr. Tabak’s long tenure and broad experience at the NIH will ensure that the agency is in capable hands and serve it well during the search for Dr. Collins’ successor,” Xavier Becerra, secretary of the Department of Health and Human Services, says in a press release announcing the appointment . HHS oversees the NIH. “Dr. Tabak has a deep grasp of the most pressing scientific issues confronting

NIH Director Will Leave Lasting Mark on Cancer.

After 12 years at the helm of the NIH, geneticist Francis Collins, MD, PhD, announced plans on October 5 to step down as the agency's director by the end of 2021.

NIH director Francis Collins to step down

NIH director Francis Collins to step down

NIH director Francis Collins to step down

NIH director Francis Collins to step down

C&EN talks with Francis Collins, chemist and NIH director

The COVID-19 vaccines authorized in the US are amazingly effective at preventing serious COVID-19 infections and death—but only if people get them. Vaccination rates remain stubbornly low in certain areas. With the more contagious Delta variant sweeping through the population, hospitals in places like Florida, Louisiana, and Missouri have been overwhelmed by COVID-19 patients. An effective antiviral—ideally a cocktail of them—could help those still vulnerable to the virus and be a critical tool if a variant emerges that evades current vaccines. Despite the gargantuan efforts to test already-approved drugs for their potential to kill the virus, researchers found very few actually worked. Today, the only approved small-molecule antiviral for COVID-19 is Gilead Sciences’ remdesivir. Its efficacy is modest at best , and its intravenous delivery makes it suitable only for people already hospitalized with the virus. A handful of newer drug candidates are currently being tested, but even assuming their

Cytomegalovirus Infections in Ugandan Infants:Newborns, Neonates with Sepsis and Infants with Hydrocephalus

Background: Congenital and postnatal cytomegalovirus (CMV) infections in Uganda is prevalent and may compromise the health of Ugandan children. The objective of this study is to estimate the prevalence of CMV infections in newborns, neonates with sepsis, and infants with hydrocephalus in Uganda. Methods: Three populations: (1) newborn-mother pairs, (2) neonates with sepsis, and (3) infants (≤ 3 months) with non-postinfectious (NPIH) or postinfectious (PIH) hydrocephalus, were evaluated over four years (2016-2019) for CMV infection at three medical centers – two in the Eastern (Mbale) and one in Western (Mbarara) Uganda. To characterize the prevalence of CMV we used quantitative PCR (qPCR) analysis. In newborn-mother pairs maternal blood (n=99) and a subset of matching cord blood (n=92), placental tissue (n=99), and vaginal specimens (n=99) were tested for CMV. In neonates and infants aged 3 months or less, peripheral blood (751 with sepsis, 399 with hydrocephalus) and cerebrospinal fluid samples (560 with sepsis, 399 with hydrocephalus (205 PIH, 194 NPIH) were also tested for CMV. Findings: The overall CMV prevalence across all groups was 9%. In newborn-mother pairs, a 3% (n=3/92; 95% CI, 1-9%) prevalence of cord blood positivity and 33% (n=33/99; 95% CI, 24-44%) prevalence of maternal vaginal shedding of CMV was estimated. In neonates with clinical sepsis, a 2% (n=17/751; 95% CI, 1-4%) CMV prevalence was estimated. Maternal HIV seropositivity (adjusted odds ratio [aOR], 21.09; 95% CI, 4-109; p= 0.0002), residence in Eastern Uganda (aOR, 11.10; 95% CI, 3-77; p=0 .003), maternal age < 25 years (aOR, 4.91; 95% CI, 2-20; p=0.012), and older neonatal age (9 days vs. 5 days; p= 0.006) were associated with CMV in neonates with clinical sepsis. In infants with PIH, the prevalence in blood was 24% (n=50/205; 95% CI, 19-31%) and in infants with NPIH it was 20% (n=39/194; 95% CI, 15-26%; p=0.34). CMV was present in the CSF of 13% (n=26/205; 95% CI, 8-18%) of infants with PIH compared to 0.5% of infants with NPIH (n=1/194; 95% CI, 0-3%, p<0.0001). Interpretation: Our findings highlight that congenital and postnatal CMV prevalence is high in this African setting and the associated complications may be significant. Universal testing and longitudinal studies are critical to understand the burden infant CMV has in sub-Saharan African countries. Funding Statement: U.S. National Institutes of Health (N.I.H) Director’s Pioneer Award 5DP1HD086071 and NIH Director’s Transformative Award 1R01AI145057. Declaration of Interests: No conflict of interest reported. Ethics Approval Statement: For all participants, mothers had to be at least 18 years of age and able to give informed written consent in either English, Lumasaba, Lugwere, Luganda, Ateso or Runyankole. The study was performed with approval from the CCHU Institutional Review Board, the Mbarara University of Science and Technology Research Ethics Committee, the Pennsylvania State University Institutional Review Board, and with oversight from the Ugandan National Council on Science and Technology. Material Transfer Agreements and a US Centers for Disease Control permit were obtained for the proper transfer and importation of samples to the Pennsylvania State University.

A New Centrifugation-Free Approach for Reducing IgA Levels in Units of Stored Red Blood Cells

Introduction: Washed red blood cells (RBCs) are indicated for immunoglobulin A (IgA) deficient recipients when RBCs from IgA-deficient donors are not available. Centrifugation-based cell processors commonly used by hospital blood banks cannot consistently reduce IgA to levels suitable for IgA-deficient recipients in a single washing cycle, hence double washing is frequently required. Additionally, cell processors are designed to wash one RBC unit at a time, making washing several units for a multiple-unit transfusion a laborious, lengthy and logistically difficult process. Importantly, these conventional cell washers are complex, expensive machines that may not be available in smaller medical facilities, thus limiting availability of washed RBCs on demand. To address these limitations, we developed a simple, portable, disposable system capable of washing stored RBC units at practical volumetric throughput without the use of centrifugation, while reducing IgA below 0.05 mg/dL in a single run. This new washing system consists of two core modules: (i) a coil of narrow-bore plastic tubing with three sequential bifurcations for high-throughput separation of washed RBCs from washing solution, and (ii) a highly-engineered membrane-hydrogel composite for concentrating the suspension of washed RBCs to the desired level of hematocrit.Materials and Methods: Several units of stored RBCs (n = 4, leukoreduced, 4-6 weeks storage duration) were purchased from the Gulf Coast Regional Blood Center (Houston, TX). Samples of stored RBCs were withdrawn from the units and diluted with 0.9% saline to a hematocrit (Hct) of 10%, to match the dilution typically used in the conventional centrifugation-based washing procedure (2000 mL of saline per typical 350 mL RBC unit with a 60-65% initial Hct). The diluted RBC samples were then washed either by our new washing system, or via conventional centrifugation. The efficiency of the two washing methods was quantified and compared by measuring several key in vitro quality metrics.Results and Discussion: Stored RBCs were diluted to 10% Hct with normal saline and passed through the new washing system at 5.0 mL/min to produce washed RBCs with output Hct of about 42%, and Hct of washing solution (waste) of about 2%. Overall, washing performed by either of the two methods substantially reduced hemolysis, lowered the concentration of free hemoglobin (by >4-fold) and total free protein (by >10-fold), while keeping the intracellular ATP unchanged (Table 1). Washing increased the fraction of well-preserved cells (discocytes, echinocytes 1) from 62.9 ± 14.3% in the initial RBC units to 74.1 ± 6.9% for our experimental device, which was a more pronounced improvement than for conventional centrifugation (67.8 ± 5.1%), although the difference was not statistically significant. Importantly, our new washing system reduced the level of IgA to well below 0.05 mg/dL required by AABB in a single pass, significantly outperforming the traditional, centrifugation-based washing procedure.Conclusions: This study demonstrated the feasibility of washing stored RBCs in normal saline for transfusion to patients with selective IgA deficiency without the use of centrifugation. Our inexpensive, portable, disposal system was significantly better than centrifugation in reducing the IgA level, and performed on par with the conventional procedure for all other key in vitro metrics of RBC quality. The ability of this new washing system to operate in line with existing infusion equipment at bedside could be particularly attractive in remote or resource-limited settings, when conventional centrifugation-based cell washers are unavailable.Acknowledgments: This work was supported by the 2012 NIH Director's Transformative Research Award (R01HL117329). [Display omitted] DisclosuresShevkoplyas:Halcyon Biomedical Incorporated: Employment, Equity Ownership, Patents & Royalties: U.S. Patent Appl. 61/929,357, Research Funding; New Health Sciences, Inc.: Consultancy, Research Funding.

028 Sleep loss disrupts hippocampal memory consolidation via an acetylcholine- and somatostatin interneuron-mediated inhibitory gate

Abstract Introduction Sleep loss profoundly disrupts consolidation of hippocampus-dependent memory. To better characterize effects of learning and sleep loss on the hippocampal circuit, we quantified activity-dependent phosphorylation of ribosomal subunit S6 (pS6) across the dorsal hippocampus of mice. Methods We first measured pS6 throughout the hippocampus after learning (single trial contextual fear conditioning; CFC), and after subsequent sleep or sleep deprivation (SD). To characterize cell populations with activity affected by SD, we used translating ribosome affinity purification (TRAP)-seq to identify cell type-specific transcripts on pS6 ribosomes after SD vs. sleep. We next used pharmacogenetics to mimic the effects of SD, selectively activating hippocampal Sst+ interneurons or cholinergic inputs to hippocampus from the medial septum (MS) while mice slept in the hours following CFC. We also inhibited these neuronal populations to assess effects on memory consolidation. Results We find that pS6 in enhanced in the dentate gyrus (DG) following single-trial CFC, but is reduced throughout the hippocampus after brief SD – a manipulation which disrupts contextual fear memory (CFM) consolidation. Cell type-specific enrichment analysis (CSEA) of these transcripts revealed that hippocampal somatostatin-expressing (Sst+) interneurons, and cholinergic and orexinergic inputs to hippocampus, are selectively activated after SD. We used TRAP targeted to hippocampal Sst+ interneurons to identify cellular mechanisms mediating SD-driven Sst+ interneuron activation. . We find that activation of Sst+ interneurons is sufficient to disrupt CFM consolidation, by gating activity in surrounding pyramidal neurons, while inhibition of Sst+ interneurons enhances memory consolidation. Similarly, pharmacogenetic activation of cholinergic input to hippocampus from the MS disrupted CFM. Inhibition of MS cholinergic neurons promoted CFM consolidation and disinhibited neurons in the DG, increasing pS6 expression among DG granule cells. Conclusion Our data suggest that state-dependent gating of DG activity during SD is mediated by cholinergic input. Together these data provide evidence for an inhibitory gate on hippocampal information processing, which is activated by sleep loss. Support (if any) R01-NS118440 to SJA from NINDS, DP2-MH104119 to SJA from the NIH Director’s Office, and a Human Frontiers Science Program Young Investigator Award

10 STARTUPS TO WATCH 2021: Early-stage companies advance precision medicine by applying AI, clinical genomics, and other new technologies

10 STARTUPS TO WATCH 2021: Early-stage companies advance precision medicine by applying AI, clinical genomics, and other new technologies