Research advances from the National Institutes of Health (NIH) Intramural Research Program (IRP) often make headlines. Read the news releases that describe our most recent findings:
BETHESDA, Md. (AP) — Sam Srisatta, a 20-year-old Florida college student, spent a month living inside a government hospital here last fall, playing video games and allowing scientists to document every morsel of food that went into his mouth.
From big bowls of salad to platters of meatballs and spaghetti sauce, Srisatta noshed his way through a nutrition study aimed at understanding the health effects of ultraprocessed foods, the controversial fare that now accounts for more than 70% of the U.S. food supply. He allowed The Associated Press to tag along for a day.
“Today my lunch was chicken nuggets, some chips, some ketchup,” said Srisatta, one of three dozen participants paid $5,000 each to devote 28 days of their lives to science. “It was pretty fulfilling.”
Examining exactly what made those nuggets so satisfying is the goal of the widely anticipated research led by National Institutes of Health nutrition researcher Kevin Hall.
“What we hope to do is figure out what those mechanisms are so that we can better understand that process,” Hall said.
Researchers have found the “Eat, Sleep, Console” (ESC) care approach to be more effective than using the Finnegan Neonatal Abstinence Scoring Tool (FNAST) to assess and manage opioid-exposed newborns, according to a national, randomized controlled clinical trial funded by the National Institutes of Health. Newborns cared for with ESC were medically ready for discharge approximately 6.7 days earlier and 63% less likely to receive medication as part of their treatment, compared to newborns cared for with FNAST. ESC prioritizes non-pharmacologic approaches to care, such as a low-stimulation environment, swaddling, skin-to-skin contact and breastfeeding. ESC also encourages parental involvement in the care and assessment of their infants. These findings are based on the hospital outcomes of a large and geographically diverse group of opioid-exposed infants. A two-year follow-up study of a subset of infants is ongoing. The current findings are published in the New England Journal of Medicine.
“Medical care for newborns who were exposed to opioids during pregnancy varies widely across hospitals,” said Diana W. Bianchi, M.D., director of NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), which co-led the study with the NIH Environmental Influences on Child Health Outcomes (ECHO) Program. “These findings are an important step toward standard, evidence-based guidance for the care of these infants.”
Opioid-exposed newborns may develop symptoms of neonatal opioid withdrawal syndrome (NOWS), which includes tremors; excessive crying and irritability; and problems with sleeping and feeding. For the past 50 years, FNAST has been the traditional assessment tool for infants with NOWS. FNAST is an extensive scoring system that assesses signs of withdrawal in more than 20 areas. Concerns have been raised about its subjectivity and overestimation of the need for opioid medication.
Results from a clinical trial conducted by researchers at the National Institutes of Health (NIH) show that people with low-grade lymphomatoid granulomatosis who are treated with interferon alfa-2b, a type of immunotherapy, can live for decades after diagnosis. Lymphomatoid granulomatosis is a rare precancerous condition triggered by Epstein-Barr virus infection. Left untreated, the disease can progress to a high-grade form, which has a poorer prognosis and can quickly turn into an aggressive and fatal B-cell lymphoma.
In the phase 2 trial, led by researchers in the Center for Cancer Research at the National Cancer Institute (NCI), part of NIH, patients treated with interferon alfa-2b lived for a median of about 20 years. By contrast, past studies reported a median survival of less than two years for people with lymphomatoid granulomatosis.
The findings suggest that immunotherapy can prevent the progression of low-grade disease to high-grade disease. The results were published March 31, 2023, in Lancet Haematology.
“We have shown in this rare disorder that using a novel immunotherapy-based approach for low-grade disease is effective and improves survival compared with historical treatments such as chemotherapy and corticosteroids,” said Christopher J. Melani, M.D., of NCI’s Center for Cancer Research, who co-led the study. “I think the results of this study represent a significant contribution to determining the standard-of-care treatment for this rare disease.”
Treatment with interferon alfa-2b led to the disappearance of a large lesion (top image) in the lungs of a patient with lymphomatoid granulomatosis, as shown in this computed tomography chest scan.
Medication is the first to reduce bone-weakening process in patients with fibrous dysplasia
A clinical trial at the National Institutes of Health found that a medication, denosumab, significantly reduced abnormal bone turnover in adults with fibrous dysplasia, a rare disease marked by weak and misshapen bones. Bone turnover, a process in which old bone is continuously replaced with new bone, is unusually accelerated in fibrous dysplasia and contributes to bone abnormalities. The study of eight participants was carried out by researchers from the National Institute of Dental and Craniofacial Research (NIDCR) and the NIH Clinical Center. The results, which showed that denosumab may improve patients’ quality of life by enabling healthy bone formation, were published as a correspondence report in the New England Journal of Medicine.
Fibrous dysplasia stems from gene mutations that cause scar-like (fibrous) tissue to replace healthy bone starting in early childhood. These fibrous lesions, which are marked by accelerated bone turnover, weaken bones, leading to bone deformities, fractures, physical disabilities, and pain. In some cases, the lesions can press up against organs and nerves, impairing functions like vision and breathing.
“Surgery is still the standard treatment for fractures and deformities caused by fibrous dysplasia,” said senior author Alison Boyce, M.D., a clinical investigator at NIDCR. “Denosumab is the first medication that appears to affect how fibrous dysplasia lesions behave and improves patients’ disease outcomes.”
Bone scans of a patient before (left) and after (right) a six-month denosumab treatment show reduced turnover within fibrous dysplasia lesions (dark-colored patches).
A study from the National Eye Institute (NEI) identified rare genetic variants that could point to one of the general mechanisms driving age-related macular degeneration (AMD), a common cause of vision loss in older adults. The variants generate malformed proteins that alter the stability of the membrane attack complex (MAC), which may drive a chronic inflammatory response in the retina. The findings, published in the journal iScience, point to MAC as a potential therapeutic target to slow or prevent the development of AMD. NEI is part of the National Institutes of Health.
There are many known genetic variants that raise or lower an individual’s risk of getting AMD; however, the contribution of each of these genetic changes to AMD is small.
To discover genetic variants — and proteins — with a direct tie to the disease, Anand Swaroop, Ph.D., chief of NEI’s Neurobiology, Neurodegeneration and Repair Laboratory, and lead author of the study, undertook a collaboration with Michael Klein, M.D., a leading AMD clinician at the Oregon Health Sciences University (OHSU), Portland. Klein has collected clinical information for hundreds of patients, as well as families with a high number of individuals with AMD. Swaroop, Klein and colleagues looked for families carrying very rare AMD-causing variants, where the effect of the gene variant is very strong, and where the variant directly affects protein structure and function. This type of rare variant can reveal the root cause of disease.
Strategy may speed delivery of therapeutic options relative to time it would take to develop gene therapies
A National Institutes of Health team has identified a compound already approved by the U.S. Food and Drug Administration that keeps light-sensitive photoreceptors alive in three models of Leber congenital amaurosis type 10 (LCA 10), an inherited retinal ciliopathy disease that often results in severe visual impairment or blindness in early childhood.
LCA 10 is caused by mutations of the cilia-centrosomal gene (CEP290). Such mutations account for 20% to 25% of all LCA — more than any other gene. In addition to LCA, CEP290 mutations can cause multiple syndromic diseases involving a range of organ systems.
Using a mouse model of LCA10 and two types of lab-created tissues from stem cells known as organoids, the team screened more than 6,000 FDA-approved compounds to identify ones that promoted survival of photoreceptors, the types of cells that die in LCA, leading to vision loss. The high-throughput screening identified five potential drug candidates, including Reserpine, an old medication previously used to treat high blood pressure.
In LCA10, CEP290 mutations lead to defects in the photoreceptor outer segment. Consequently, the building blocks of the primary cilium accumulate in the photoreceptors, which activates autophagy (shown left, untreated). Reserpine restores the balance between autophagy and the ubiquitin-proteasome system histone deacetylase 6 and improves primary cilium assembly.
Scientists have identified an autoinflammatory disease caused by mutations in the LYN gene, an important regulator of immune responses in health and disease. Named Lyn kinase-associated vasculopathy and liver fibrosis (LAVLI), the identification sheds light on how genes linked to certain illnesses can potentially be targets for treatment by repurposing existing drugs. The research, published in Nature Communications, was led by Adriana A. de Jesus, M.D. Ph.D., and Raphaela Goldbach-Mansky, M.D., M.H.S., of the Translational Autoinflammatory Diseases Section of the Laboratory of Clinical Immunology and Microbiology at the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health.
LAVLI was first discovered in a pediatric patient through genetic testing, which detected a mutation in LYN, the gene that encodes the Lyn kinase protein. Two additional, unrelated pediatric patients were later discovered to have two more mutations in the same gene. All three patients developed diseases linked to the LYN genetic mutation shortly after birth. Two patients developed liver fibrosis — excessive amounts of scar tissue caused by inflammation and repeated liver damage — in the first year of life. All three patients had perinatal onset of neutrophilic cutaneous small vessel vasculitis. This is an immune disorder characterized by inflammation from high numbers of neutrophils — white blood cells of the immune system — that can damage small blood vessels. The study revealed Lyn kinase was always active and unable to shut down in the three patients with the LYN mutation, which increased neutrophil migration, altered inflammatory signals and activated scar and fibrosis-inducing liver cells. The results of this study suggest that Lyn kinase may be a potential therapeutic target for drugs that treat forms of non-syndromic small vessel vasculitis and other types of inflammation-induced liver fibrosis.
Lesional skin biopsy shows co-expression of the endothelial marker CD31 and the activation/adhesion marker, ICAM1, in focal areas of a small vessel in the skin in Patient 1.
New mouse model may inform potential therapeutic options for Down syndrome
National Institutes of Health researchers compared a new genetic animal model of Down syndrome to the standard model and found the updated version to be more similar to the changes seen in humans. The new mouse model shows milder cognitive traits compared to a previously studied Down syndrome mouse model. The results of this study, published in Biological Psychiatry, may help researchers develop more precise treatments to improve learning and memory in people with Down syndrome.
Scientists found that the new mouse model, known as Ts66Yah, had memory difficulties and behavior traits, but the symptoms were not as severe as seen with the previous mouse model. Scientists often use different strains of mice as animal models to study human diseases because most genes in humans have similar counterparts in mice.
The new mouse model, known as Ts66Yah, has a minichromosome with over a hundred genes from mouse chromosome 16 attached to the centromere region of mouse chromosome 17. These genes are most relevant to human chromosome 21.
Results in cell and mouse studies may have implications for the development of a new class of anticancer drugs
Scientists at the National Institutes of Health and Massachusetts General Hospital in Boston have uncovered a potential new approach against liver cancer that could lead to the development of a new class of anticancer drugs. In a series of experiments in cells and mice, researchers found that an enzyme produced in liver cancer cells could convert a group of compounds into anticancer drugs, killing cells and reducing disease in animals.
The researchers suggest that this enzyme could become a potential target for the development of new drugs against liver cancers, and perhaps other cancers and diseases as well.
“We found a molecule that kills cells in a rare liver cancer in a unique way,” said translational scientist Matthew Hall, Ph.D., one of the leaders of the work at NIH’s National Center for Advancing Translational Sciences (NCATS). “It emerged from a screening to find molecules that selectively kill human liver cancer cells. It took a lot of work to figure out that the molecule is converted by an enzyme in these liver cancer cells, creating a toxic, anticancer drug.”
NCATS scientists used the Center’s drug screening capabilities, including drug screening plates like those shown here, to identify a molecule that was effective in killing liver cancer cells. Researchers determined that a specific enzyme was key to turning the molecule into a potential anticancer drug.
A small portion of adults in remission from a deadly blood cancer had persisting mutations that were detected, which predicted their risk of death from having the cancer return
Researchers at the National Institutes of Health show the benefits of screening adult patients in remission from acute myeloid leukemia (AML) for residual disease before receiving a bone marrow transplant. The findings, published in JAMA, support ongoing research aimed at developing precision medicine and personalized post-transplant care for these patients.
About 20,000 adults in the United States are diagnosed each year with AML, a deadly blood cancer, and about one in three live past five years. A bone marrow transplant, which replaces unhealthy blood-forming cells with healthy cells from a donor, often improves these chances. However, research has shown that lingering traces of leukemia can make a transplant less effective.
Researchers in the current study wanted to show that screening patients in remission for evidence of low levels of leukemia using standardized genetic testing could better predict their three-year risks for relapse and survival. To do that, they used ultra-deep DNA sequencing technology to screen blood samples from 1,075 adults in remission from AML. All were preparing to have a bone marrow transplant. The study samples were provided through donations to the Center for International Blood and Marrow Transplant Research.
After screening adults with variants commonly associated with AML, researchers showed that the two most common mutations in AML —NPM1 and FLT3-ITD — could be used to track residual leukemia. Among 822 adults with these variants detectable at initial diagnosis, 142 adults — about one in six — were found to still have residual traces of these mutations after therapy despite being classified as in remission.
The American Association for the Advancement of Science (AAAS) elected 505 scientists, engineers, and innovators from around the world and across all disciplines to its 2022 class of fellows. Ten NIH scientists are among the electees: Dr. Linda S. Birnbaum (NIEHS), Dr. Carmen Williams (NIEHS), Dr. Cynthia Dunbar (NHLBI), Dr. Howard Young (NCI), Dr. Eric Engels (NCI), Dr. Elodie Ghedin (NIAID), Dr. Paul Liu (NHGRI), Dr. Lee Scott Weinstein (NIDDK), Dr. Karen Faith Berman (NIMH), and Dr. Christopher McBain (NICHD).
AAAS is the world’s largest general scientific society and publisher of the Science family of journals. Newly elected fellows are recognized for scientific and socially notable achievements spanning their careers. Election is one of the most distinguished honors in the scientific community.
AAAS fellows are a distinguished cadre who have been recognized for their achievements across disciplines, from research, teaching and technology, to administration in academia, industry and government, to excellence in communicating and interpreting science to the public.
In a tradition stretching back to 1874, individuals are elected annually by the AAAS council. New fellows are recognized at a ceremonial forum during the AAAS annual meeting, where they are presented with a certificate and blue and gold rosette.
