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:
Whether you’re shedding pounds with the help of effective new medicines, slimming down after weight loss surgery or cutting calories and adding exercise, there will come a day when the numbers on the scale stop going down, and you hit the dreaded weight loss plateau.
In a recent study, Kevin Hall, a researcher at the National Institutes of Health who specializes in measuring metabolism and weight change, looked at when weight loss typically stops depending on the method people were using todrop pounds. He broke down the plateau into mathematical models using data from high-quality clinical trials of different ways to lose weight to understand why people stop losing when they do. The study published Monday in the journal Obesity.
Scientists from two independent research teams have discovered how the mislocalization of a protein, known as TDP-43, alters the genetic instructions for UNC13A, providing a possible therapeutic target that could also have implications in treating amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and other forms of dementia. ALS and FTD are two neurodegenerative disorders in which many cases are linked by mislocalization of TDP-43, where instead of being primarily located in the nucleus of the cell where genes are activated, it forms aggregates outside the nucleus in multiple neurodegenerative diseases. Rare mutations in the TDP-43 gene are known to cause ALS, but almost all cases of ALS show mislocalization of TDP-43. The studies were published in Nature.
“ALS and FTD patients have long participated in genetic studies looking for changes in genes that might contribute to risk for disease,” said Thomas Cheever, Ph.D., program director at the National Institute of Neurological Disorders and Stroke (NINDS). “Here, we see two independent research teams converging to explain how one of these changes can be a critical factor contributing to an entire class of neurodegenerative diseases, as well as a potential therapeutic target.”
One study, which is a collaboration between the labs of Michael Ward, M.D., Ph.D., scientist at the National Institutes of Health’s NINDS, and Pietro Fratta, Ph.D., professor at the University College London Queen Square Motor Neuron Disease Centre in the United Kingdom, initially looked at lab-grown neurons derived from human induced pluripotent stem cells (iPSCs) — stem cells created from a patient’s tissue sample, often skin or blood. Using powerful genetic tools, the researchers created neurons that made much less TDP-43 protein than normal, and this resulted in the appearance of abnormal mRNA sequences inserted into the instructions used to make several other proteins. These abnormally inserted sequences, called cryptic exons, can result in a defective protein or can even prevent the protein from being made at all.
Study highlights the need for public health messaging strategies that address biases against all population groups that have been marginalized
People from all major racial and ethnic minority population groups in the United States report experiencing more COVID-19–related discrimination than white adults, a new study shows. COVID-19-related discrimination includes experiences of being threatened or harassed based on someone’s perception of another having COVID-19. To date, this is the largest study, with the most diverse participants, to examine discrimination related to COVID-19. The study was led by Paula D. Strassle, Ph.D., of the National Institute on Minority Health and Health Disparities (NIMHD), part of the National Institutes of Health, and was published in the American Journal of Public Health on Feb. 23, 2022.
In the study, researchers measured the prevalence of COVID-19–related discrimination in all major racial and ethnic groups in the United States, using data from the COVID-19’s Unequal Racial Burden (CURB) survey. They also analyzed the impact of other social and demographic factors on COVID-19–related discrimination. People from groups that have been marginalized, such as those who speak little to no English and those with lower levels of education, were also found to face more discrimination due to the pandemic.
Researchers collected information from 5,500 American Indian/Alaska Native, Asian, Black/African American, Hawaiian and Pacific Islander, Latino, white, and multiracial adults. The online survey was administered by YouGov from December 2020 to February 2021 and was available in English and Spanish. The survey asked whether participants had experienced COVID-19–related discriminatory behaviors, such as being called names or insulted, being threatened or harassed, or hearing racist comments, because the perpetrator thought the participant had COVID-19. The survey also asked whether participants felt that others acted afraid of them because they belonged to a racial/ethnic group misconceived to get COVID-19 more often.
After studying blood samples from 244 patients hospitalized for COVID-19, a group of researchers, including those who work at the National Institutes of Health, identified “rogue antibodies” that correlate with severe illness and may help explain mechanisms associated with severe blood clotting. The researchers found circulating antiphospholipid antibodies, which can be more common among people with autoimmune disorders, such as lupus. However, these “autoantibodies,” which target a person’s own organs and systems, can also be activated in response to viral infections and activate other immune responses.
Scientists compared the blood samples to those from healthy controls and found the COVID-19 samples contained higher levels of the antibody IgG, which works with other immune cells, such as IgM, to respond to immune threats. Higher levels of IgG were also associated with COVID-19 disease severity, such as in patients who required breathing assistance. The researchers observed similar patterns, but to a lesser extent, after analyzing blood samples from 100 patients hospitalized for sepsis, which can leave the body in inflammatory shock following a bacterial or viral infection.
IgG helps bridge a gap between innate and adaptive immune responses – a process that helps the body recognize, respond to, and remember danger. In normal cases, these features help protect the body from illness and infection. However, in some cases, this response can become hyperextended or altered and exacerbate illness. A unique finding from this study is that when researchers removed IgG from the COVID-19 blood samples, they saw molecular indicators of “blood vessel stickiness” fall. When they added these same IgG antibodies to the control samples, they saw a blood vessel inflammatory response that can lead to clotting.
National Institutes of Health researchers, led by Dr. Steven Rosenberg, MD, Ph.D., chief of the Surgery Branch at the Center for Cancer Research, National Cancer Institute (NCI), have found unique expression profiles in 50 genes that help identify rare anti-tumor lymphocytes that can infiltrate and help defeat metastatic solid epithelial tumors. To develop these profiles, a highly sensitive assay was designed that identified tumor-infiltrating lymphocytes (TIL) with cell surface receptors that can recognize the products of the very mutations that caused the cancer. The identification of these lymphocytes could help advance the development and effectiveness of personalized cancer immunotherapies for patients whose cancers do not respond to standard treatments.
This finding in TILs is especially important because it is agnostic to the type of tumor a patient has – it seems to have promise in stomach, esophageal, ovarian and breast cancers, among other types of tumors.
An experimental form of immunotherapy that uses an individual’s own tumor-fighting immune cells could potentially be used to treat people with metastatic breast cancer, according to results from an ongoing clinical trial led by researchers at the National Cancer Institute’s (NCI) Center for Cancer Research, part of the National Institutes of Health. Many people with metastatic breast cancer can mount an immune reaction against their tumors, the study found, a prerequisite for this type of immunotherapy, which relies on what are called tumor-infiltrating lymphocytes (TILs).
In a clinical trial of 42 women with metastatic breast cancer, 28 (or 67%) generated an immune reaction against their cancer. The approach was used to treat six women, half of whom experienced measurable tumor shrinkage. Results from the trial appeared Feb. 1, 2022, in the Journal of Clinical Oncology.
“It’s popular dogma that hormone receptor–positive breast cancers are not capable of provoking an immune response and are not susceptible to immunotherapy,” said study leader Steven A. Rosenberg, M.D., Ph.D., chief of the Surgery Branch in NCI’s Center for Cancer Research. “The findings suggest that this form of immunotherapy can be used to treat some people with metastatic breast cancer who have exhausted all other treatment options.”
Before TIL therapy, a woman with breast cancer had metastatic lesions in her chest wall (top, left) and liver (bottom, left). After receiving the immunotherapy, her tumors shrank completely, and recent scans (right) show that she remains cancer free more than five years later.
Research sheds light on severity for gene variants; establishes outcome measures for therapeutic trials
National Eye Institute researchers developed and validated an artificial-intelligence-based method to evaluate patients with Stargardt, an eye disease that can lead to childhood vision loss. The method quantifies disease-related loss of light-sensing retina cells, yielding information for monitoring patients, understanding genetic causes of the disease, and developing therapies to treat it. The findings published today in JCI Insight.
“These results provide a framework to evaluate Stargardt disease progression, which will help control for the significant variability from patient to patient and facilitate therapeutic trials,” said Michael F. Chiang, M.D., director of the NEI, which is part of the National Institutes of Health.
About 1 in 9,000 people develop the most common form of Stargardt, or ABCA4-associated retinopathy, an autosomal-recessive disease caused by variants to the ABCA4 gene, which contains genetic information for a transmembrane protein in light-sensing photoreceptor cells. People develop Stargardt when they inherit two mutated copies of ABCA4, one from each parent. People who have just one mutated copy of ABCA4 are genetic carriers, but do not develop the disease. More rare forms of Stargardt are associated with variants of other genes.
Spectral-domain optical coherence tomography uses light to image layers of the retina. Many scans taken over five years were analyzed using deep learning, a type of artificial intelligence in which imaging data are fed into an algorithm that learns how to detect patterns. Six retinal layers were segmented and analyzed for changes in thickness.
Small NIH study contributes to understanding of COVID-19 during pregnancy
SARS-CoV-2 infection during pregnancy may cause inflammatory immune responses in the fetus, even if the virus does not infect the placenta, according to a small National Institutes of Health study. Researchers describe unique maternal, fetal, and placental immune responses among pregnant women with COVID-19 in a study led by NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). The findings detail changes in antibodies, immune cell types and inflammatory markers in maternal blood, umbilical cord blood and placental tissues. The study is published in the journal Nature Communications.
People who are pregnant are at a higher risk for severe illness from COVID-19, compared to people who are not pregnant. COVID-19 during pregnancy also increases the risk for preterm birth, stillbirth and preeclampsia. Therefore, understanding COVID-19 infection during pregnancy is important to help healthcare providers optimize the health and safety of their patients during the pandemic.
The study evaluated 23 pregnant women. Twelve were positive for SARS-CoV-2, and of these, eight were asymptomatic, one had mild symptoms and three had severe COVID-19. After delivery, the researchers compared immune responses between mothers and their newborns by comparing maternal blood and umbilical cord blood. Inflammatory immune responses triggered by the virus were observed in women, their neonates and placental tissues regardless of whether the mothers had symptoms.
Use of patient-derived stem cells will enable high-throughput drug screening for potential therapeutics
Researchers at the National Eye Institute (NEI) have developed the first patient-derived stem cell model for studying eye conditions related to oculocutaneous albinism (OCA). The model’s development is described in the January issue of the journal Stem Cell Reports. NEI is part of the National Institutes of Health.
“This ‘disease-in-a-dish’ system will help us understand how the absence of pigment in albinism leads to abnormal development of the retina, optic nerve fibers, and other eye structures crucial for central vision,” said Aman George, Ph.D., a staff scientist in the NEI Ophthalmic Genetics and Visual Function Branch, and the lead author of the report.
OCA is a set of genetic conditions that affects pigmentation in the eye, skin, and hair due to mutation in the genes crucial to melanin pigment production. In the eye, pigment is present in the retinal pigment epithelium (RPE), and aids vision by preventing the scattering of light. The RPE is located right next to the eye’s light-sensing photoreceptors and provides them nourishment and support. People with OCA lack pigmented RPE and have an underdeveloped fovea, an area within the retina that is crucial for central vision. The optic nerve carries visual signals to the brain.
A human induced pluripotent stem cell colony from OCA1A patient. The image was acquired using a confocal microscope and is stained for pluripotency marker proteins. The red color depicts transcription factor OCT4, green is SSEA4 protein, and blue represents the nucleus of the cells.
A diet rich in fiber may help some people being treated for melanoma respond to immunotherapy treatment by influencing the gut microbiome, according to a new study led by researchers at the Center for Cancer Research at the National Cancer Institute (NCI), part of the National Institutes of Health, and the University of Texas MD Anderson Cancer Center. Results from the study, which analyzed both people with melanoma and mouse models of the disease, appear in Science.
Among patients with advanced melanoma who underwent immunotherapy with immune checkpoint blockers, those who consumed at least 20 grams a day of dietary fiber survived the longest without their disease progressing. In contrast, use of probiotic supplements appeared to lessen somewhat the effectiveness of immune checkpoint blocker regimens. Probiotics are live microorganisms typically consumed as a supplement to improve gut health.
“The data suggest that one can target the composition of the gut microbiota and affect the ability of the patient to respond to immunotherapy,” said Giorgio Trinchieri, M.D., chief of the Laboratory of Integrative Cancer Immunology in NCI’s Center for Cancer Research, one of the study’s coleaders. “Consuming a diet rich in fiber, like fruits, vegetables, and legumes, could improve your ability to respond to immunotherapy.”
Human and animal study offers insight into treating periodontal disease and other inflammatory disorders
Blocking function of a blood-clotting protein prevented bone loss from periodontal (gum) disease in mice, according to research led by scientists at the National Institute of Dental and Craniofacial Research (NIDCR), part of the National Institutes of Health. Drawing on animal and human data, the researchers found that buildup of the protein, called fibrin, triggers an overactive immune response that damages the gums and underlying bone. The study, which was published in Science, suggests that suppressing abnormal fibrin activity could hold promise for preventing or treating periodontal disease, as well as other inflammatory disorders marked by fibrin buildup, including arthritis and multiple sclerosis.
Periodontal disease affects nearly half of Americans over age 30, and 70% of those 65 and older. It is a bacterial infection of the tissues supporting the teeth. In its early stages, periodontal disease causes redness and swelling (inflammation) of the gums. In advanced stages, called periodontitis, the underlying bone becomes damaged, leading to tooth loss. While scientists have known that periodontitis is driven in part by an exaggerated immune cell response, until now, it was unclear what triggered the response, and how it caused tissue and bone damage.
”Severe periodontal disease can lead to tooth loss and remains a barrier to productivity and quality of life for far too many Americans, especially those lacking adequate access to dental care,” said NIDCR Director Rena D’Souza, D.D.S., Ph.D. “By providing the most comprehensive picture yet of the underlying mechanisms of periodontal disease, this study brings us closer to more effective methods for prevention and treatment.”
Compared to healthy volunteers (left), gum tissue from people with severe periodontal disease (right) shows high levels of fibrin (magenta).
