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.
NIH researchers develop new tools to demonstrate how environmental agents can lead to diseases
Researchers have developed a three-dimensional model that shows how exposure to cadmium might lead to congenital heart disease. Affecting nearly 40,000 newborns a year, congenital heart disease is the most common type of birth defect in the United States. The model was created by scientists at the National Institute of Environmental Health Sciences (NIEHS), part of the National Institutes of Health.
Cadmium is a metal that can be released into the environment through mining and various industrial processes, and it has been found in air, soil, water, and tobacco. The metal can enter the food chain when plants absorb it from soil. Previous studies suggested that maternal exposure to cadmium might be a significant risk factor for congenital heart disease.
Using models derived from human cells and tissues, called in vitro models, researchers designed a 3D organoid model that mimics how the human heart develops. The researchers saw how exposure to low levels of cadmium can block usual formation of cardiomyocytes, which are the major type of cells that form the heart. In doing so, they revealed the biological mechanisms that might explain how cadmium could induce heart abnormalities.
“The models we created are useful for not only studying cadmium, but for studying other chemicals and substances as well,” said study lead Erik Tokar, Ph.D., from the Mechanistic Toxicology Branch of the NIEHS Division of Translational Toxicology (DTT).
2D model showing how the pluripotent stem cells react to human relevant doses of cadmium over 8 days. From the control in the first panel, to the last panel, researchers can see how the differentiation to cardiomyocytes is inhibited with different doses of cadmium.
Research explores how new information is consolidated across the sleep-wake cycle
Using a mouse model, researchers have discovered a new daily rhythm in a type of synapse that dampens brain activity. Known as inhibitory synapses, these neural connections are rebalanced so that we can consolidate new information into long-lasting memories during sleep. The findings, published in PLOS Biology, may help explain how subtle synaptic changes enhance memory in humans. The study was led by researchers at the National Institute of Neurological Disorders and Stroke (NINDS), part of the National Institutes of Health.
“Inhibition is important for every aspect of brain function. But for over two decades, most sleep studies have focused on understanding excitatory synapses,” said Dr. Wei Lu, senior investigator at NINDS. “This is the first study to try to understand how sleep and wakefulness regulate inhibitory synapses.”
In the study, Kunwei Wu, Ph.D., a postdoctoral fellow in Dr. Lu’s lab, examined what happens at inhibitory synapses during sleep and wakefulness in mice. Electrical recordings from neurons in the hippocampus — a brain region important for memory formation — showed a previously unappreciated pattern of activity. During wakefulness, steady 'tonic' inhibitory activity increased, while fast 'phasic' inhibition decreased. They also found much larger activity-dependent enhancement of inhibitory electrical responses in neurons from awake mice suggesting that wakefulness, but not sleep, could strengthen these synapses to a greater degree.
Interneurons (green) in the hippocampus of a mouse
One dose of an antibody drug safely protected healthy, non-pregnant adults from malaria infection during an intense six-month malaria season in Mali, Africa, a National Institutes of Health clinical trial has found. The antibody was up to 88.2% effective at preventing infection over a 24-week period, demonstrating for the first time that a monoclonal antibody can prevent malaria infection in an endemic region. These findings were published today in The New England Journal of Medicine and presented at the American Society of Tropical Medicine & Hygiene 2022 Annual Meeting in Seattle.
“We need to expand the arsenal of available interventions to prevent malaria infection and accelerate efforts to eliminate the disease,” said Anthony S. Fauci, M.D., director of the National Institute of Allergy and Infectious Diseases (NIAID), part of NIH. “These study results suggest that a monoclonal antibody could potentially complement other measures to protect travelers and vulnerable groups such as infants, children, and pregnant women from seasonal malaria and help eliminate malaria from defined geographical areas.”
NIAID sponsored and funded the trial, which was led by Peter D. Crompton, M.D., M.P.H., and Kassoum Kayentao, M.D., M.P.H., Ph.D. Dr. Crompton is chief of the Malaria Infection Biology and Immunity Section in the NIAID Laboratory of Immunogenetics, and Dr. Kayentao is a professor at the University of Sciences, Techniques and Technologies (USTTB) of Bamako, Mali.
An antibody drug called CIS43LS prevents malaria infection by interrupting the lifecycle of the Plasmodium falciparum parasite. The antibody binds to and neutralizes sporozoites, the stage of the parasite transmitted from mosquitos to humans.
A panel of investigational monoclonal antibodies (mAbs) targeting different sites of the Epstein-Barr virus (EBV) blocked infection when tested in human cells in a laboratory setting. Moreover, one of the experimental mAbs provided nearly complete protection against EBV infection and lymphoma when tested in mice. The results appear online today in the journal Immunity. Scientists from the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, in collaboration with researchers from Walter Reed Army Institute of Research, led the study.
EBV is one of the most common human viruses. After an EBV infection, the virus becomes dormant in the body but may reactivate in some cases. It is the primary cause of infectious mononucleosis and is associated with certain cancers, including Hodgkin lymphoma, and autoimmune diseases, such as multiple sclerosis. People with weakened immune systems, such as transplant recipients, are more likely than immunocompetent people to develop severe symptoms and complications from EBV infection. There is no licensed vaccine to protect against the virus.
The researchers developed several investigational mAbs targeting two key proteins—gH and gL—found on EBV’s surface. The two proteins are known to facilitate EBV fusion with human cells and cause infection. When tested in the laboratory setting, the investigational mAbs prevented EBV infection of human B cells and epithelial cells, which line the throat at the initial site of EBV infection. Analyzing the structure of the mAbs and their two surface proteins using X-ray crystallography and advanced microscopy, the researchers identified multiple sites of vulnerability on the virus to target. When tested in mice, one of the experimental mAbs, called mAb 769B10, provided almost complete protection against EBV infection when given. The mAb also protected all mice tested from EBV lymphoma.
An electron microscopy image showing three Epstein-Barr virions
Study may help lead to gene therapy for rare inherited blinding disease
Using a new stem-cell based model made from skin cells, scientists found the first direct evidence that Stargardt-related ABCA4 gene mutations affect a layer of cells in the eye called the retinal pigment epithelium (RPE). The discovery points to a new understanding of Stargardt disease progression and suggests a therapeutic strategy for the disease, which currently lacks treatment. The study took place at the National Eye Institute (NEI), part of the National Institutes of Health. The findings published online today in Stem Cell Reports.
“This new model will accelerate development of therapies for Stargardt disease,” said NEI Director Michael F. Chiang, M.D. “We lack a therapy for this disease in part because it’s rare. This model theoretically creates an unlimited supply of human cells for study.” Stargardt affects about 1 in every 10,000 people in the U.S.
Stargardt disease causes progressive loss of central and night vision. The vision loss is associated with the toxic build-up of lipid-rich deposits in the RPE, whose main job is to support and nourish the retina’s light sensing photoreceptors. Under normal conditions, the ABCA4 gene makes a protein that prevents this toxic build-up. Prior research showed that Stargardt disease is caused by a variety of mutations in the ABCA4 gene. More than 800 ABCA4 mutations are known to be associated with a broad spectrum of Stargardt disease phenotypes.
A cross section of the stem-cell generated RPE is shown after it has been fed photoreceptor outer segments. Arrows point to lipid deposits (green). This buildup of lipids is toxic to the cell, and similar to that seen in patients with Stargardt disease.
Scientists have discovered a mechanism by which an area of a protein shape-shifts to convert vitamin A into a form usable by the eye’s light-sensing photoreceptor cells. A previously uncharacterized area of the protein known as RPE65 spontaneously turns spiral-shaped when it encounters intracellular membranes, or thin structures that surround different parts of a cell.
This shapeshifting enables RPE65 to enter the endoplasmic reticulum — a network of sac-like structures and tubes — where RPE65 performs the crucial task of vitamin A conversion. The scientists say the discovery provides better understanding of RPE65’s function and will inform potential treatments for vision disorders linked to RPE65 gene mutations. Researchers at the National Eye Institute, part of the National Institutes of Health, conducted the research, which published in Life Science Alliance.
Women who used chemical hair straightening products were at higher risk for uterine cancer compared to women who did not report using these products, according to a new study from the National Institutes of Health. The researchers found no associations with uterine cancer for other hair products that the women reported using, including hair dyes, bleach, highlights, or perms.
The study data includes 33,497 U.S. women ages 35-74 participating in the Sister Study, a study led by the National Institute of Environmental Health Sciences (NIEHS), part of NIH, that seeks to identify risk factors for breast cancer and other health conditions. The women were followed for almost 11 years and during that time 378 uterine cancer cases were diagnosed.
The researchers found that women who reported frequent use of hair straightening products, defined as more than four times in the previous year, were more than twice as likely to go on to develop uterine cancer compared to those who did not use the products.
“We estimated that 1.64% of women who never used hair straighteners would go on to develop uterine cancer by the age of 70; but for frequent users, that risk goes up to 4.05%,” said Alexandra White, Ph.D., head of the NIEHS Environment and Cancer Epidemiology group and lead author on the new study. “This doubling rate is concerning. However, it is important to put this information into context - uterine cancer is a relatively rare type of cancer.”
NIH scientists shed light on how genetic architecture determines gene expression, tissue-specific function, and disease phenotype in blinding diseases
National Eye Institute researchers mapped the organization of human retinal cell chromatin, the fibers that package 3 billion nucleotide-long DNA molecules into compact structures that fit into chromosomes within each cell’s nucleus. The resulting comprehensive gene regulatory network provides insights into regulation of gene expression in general, and in retinal function, in both rare and common eye diseases. The study published in Nature Communications.
“This is the first detailed integration of retinal regulatory genome topology with genetic variants associated with age-related macular degeneration (AMD) and glaucoma, two leading causes of vision loss and blindness,” said the study’s lead investigator, Anand Swaroop, Ph.D., senior investigator and chief of the Neurobiology Neurodegeneration and Repair Laboratory at the NEI, part of the National Institutes of Health.
Using deep Hi-C sequencing, a tool used for studying 3D genome organization, the researchers created a high-resolution map of retinal cell chromatin contract points, shown left. The entire map included about 704 million contact points. Shown right, more than 60,000 chromatin loops are represented on a portion of the map.
Findings from a small study of eight patients published in Clinical Infectious Diseases suggest that COVID-19 rebound is likely not caused by impaired immune responses. The study, led by scientists at the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, aimed to define the clinical course and the immunologic and virologic characteristics of COVID-19 rebound in patients who have taken nirmatrelvir/ritonavir (Paxlovid), an antiviral therapeutic developed by Pfizer, Inc. COVID-19 rebound is characterized by a recurrence of COVID-19 symptoms and/or a new positive viral test after having tested negative, according to the Centers for Disease Control and Prevention. According to the study authors, the results do not support the hypothesis that the five-day course of Paxlovid is too short for the body to develop a strong immune response to SARS-CoV-2, the virus that causes COVID-19.
Participants were selected from adults enrolled in an ongoing COVID-19 study at the NIH Clinical Center in Bethesda, Maryland, and other local hospitals. The study aims to better understand how SARS-CoV-2 affects white blood cells. Participants provide blood and other samples as well as access to their COVID-19 medical records as part of the study. The study to evaluate COVID-19 rebound included six participants (three men and three women with a median age of 42 years) who took Paxlovid within four days of initial symptom onset and then experienced recurrent symptoms; two participants (a 54-year-old man and 35-year-old woman) who experienced recurrent symptoms who did not take Paxlovid; and a control group of six people who had COVID-19 but did not experience symptom rebound. All participants were previously vaccinated and boosted against COVID-19, and none developed severe disease requiring hospitalization during acute infection or rebound. Investigators collected data on each participant’s clinical course and performed laboratory tests on blood and nasal swab samples.
Investigators found no evidence of genetic mutations that would suggest participants who experienced COVID-19 rebound were infected with a strain of SARS-CoV-2 that was resistant to Paxlovid. They also found no evidence of delayed development of antibodies in participants experiencing rebound after taking Paxlovid. Investigators detected robust SARS-CoV-2 T-cell responses in rebound patients. Overall, the level of T-cell responses was greater in rebound patients than in patients with early acute COVID-19 who did not experience rebound. Infectious SARS-CoV-2 was detected by viral culture in one out of eight rebound participants.
Colorized scanning electron micrograph of a cell infected with the Omicron strain of SARS-CoV-2 virus particles (purple), isolated from a patient sample.
Monica M. Bertagnolli, M.D., started today as the 16th director of the National Cancer Institute (NCI), part of the National Institutes of Health (NIH). She is the first woman to hold the position of NCI director. Dr. Bertagnolli succeeds Norman E. Sharpless, M.D., who stepped down as director in April 2022. Douglas R. Lowy, M.D., has been NCI’s acting director since April 30, 2022.
“I look forward to working with Dr. Bertagnolli to advance the President’s call to end cancer as we know it. Dr. Bertagnolli’s decades of cancer research expertise around patient-centered care and her work to create more inclusive clinical trials will be instrumental as we accelerate the rate of research and innovation to fight cancer,” said Secretary Xavier Becerra, U.S. Health and Human Services. “Cancer knows no bounds and neither should our efforts to prevent cancer deaths. Together, we will reignite and advance the President’s Cancer Moonshot initiative to save lives.”
“Dr. Bertagnolli brings exceptional experience to NIH as a surgical oncologist, professor, scientist and leader in the cancer research community,” said Lawrence A. Tabak, D.D.S., Ph.D., who is performing the duties of the NIH director. “She is ideally suited to lead NCI at a point in time when opportunities abound for major advancements in cancer research and cancer care.”
NCI Director Dr. Monica Bertagnolli. Photo courtesty of Brigham and Women’s Hospital
