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.
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
Former smokers who stick to a healthy lifestyle have a lower risk of dying from all causes than those who don’t engage in healthy habits, according to a new study by researchers at the National Cancer Institute (NCI), part of the National Institutes of Health. The reduced risk of dying was observed for specific causes, including cancer and heart and lung diseases. Lifestyle interventions have not been robustly studied in former smokers, and these new findings could have important implications for the 52 million former smokers in the United States.
Maintaining a healthy lifestyle — defined as doing things such as being physically active and having a healthy diet — was associated with a 27% reduction in the risk of death over the 19-year follow-up period, compared with not maintaining a healthy lifestyle.
The findings, which appeared Sept. 22, 2022, in JAMA Network Open, come from an analysis of a large group of former smokers who participated in the NIH-AARP Diet and Health Study.
“I was surprised to see the robust associations [with lifestyle],” said Maki Inoue-Choi, Ph.D., of the Division of Cancer Epidemiology and Genetics at NCI, lead author of the paper. “Former smokers who adhered to evidence-based recommendations for body weight, diet, physical activity, and alcohol intake had a lower risk of mortality than former smokers who didn't adhere to these recommendations.”
A medication for heart problems and high blood pressure may also be effective for treating alcohol use disorder, according to a new study by researchers at the National Institutes of Health and their colleagues. The study presents converging evidence from experiments in mice and rats, as well as a cohort study in humans, suggesting that the medication, spironolactone, may play a role in reducing alcohol drinking. The research was led by scientists at the National Institute on Drug Abuse (NIDA) and the National Institute on Alcohol Abuse and Alcoholism (NIAAA), both parts NIH, and Yale School of Medicine, New Haven, Connecticut. A report of the new findings is published in Molecular Psychiatry.
“Combining findings across three species and different types of research studies, and then seeing similarities in those data, gives us confidence that we are onto something potentially important scientifically and clinically. These findings support further study of spironolactone as a potential treatment for alcohol use disorder, a medical condition that affects millions of people in the U.S.,” said Lorenzo Leggio, M.D., Ph.D., chief of the Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, a joint laboratory of NIDA and NIAAA, and one of the senior authors.
Currently there are three medications approved for alcohol use disorder in the United States, and they are an effective and important aid in the treatment of people with this condition. Given the diverse biological processes that contribute to alcohol use disorder, new medications are needed to provide a broader spectrum of treatment options. Scientists are working to develop a larger menu of pharmaceutical treatments that could be tailored to individual needs.
NIH study shows the role of transcription factors in facilitating cell regeneration
National Institutes of Health researchers have discovered a specific network of proteins that is necessary to restore hearing in zebrafish through cell regeneration. The study, led by investigators at the National Human Genome Research Institute (NHGRI), may inform the development of treatments for hearing loss in humans. The findings were published in Cell Genomics.
Although hair cell loss cannot be replaced in humans, many animals, including zebrafish, can restore hearing after injury through the regeneration of hair cells. The regenerative properties of zebrafish hair cells prompted researchers to use this animal to understand some fundamental properties of regeneration.
Hearing loss affects around 37.5 million Americans, and most cases come from the loss of hearing receptors known as “hair cells” in the inner ear. Bristles that stick out of these microscopic hair cells move and bend when sound travels into our ears, resulting in electric signals sent through nerves and into our brains that allow us to process sound.
Confocal image of adult zebrafish hair cells (green) in the auditory organ of the inner ear.
New findings could improve the development and efficacy of therapies
By combining traditional eye imaging techniques with adaptive optics — a technology that enhances imaging resolution — researchers at the National Eye Institute (NEI) have shown for the first time how cells across different tissue layers in the eye are affected in people with choroideremia, a rare genetic disorder that leads to blindness. Their study, which was funded by the NEI Intramural Research Program, is published in Communications Biology. NEI is part of the National Institutes of Health.
Johnny Tam, Ph.D., head of the NEI Clinical and Translational Imaging Unit combined adaptive optics with indocyanine green dye to view live cells in the retina, including light-sensing photoreceptors, retinal pigment epithelium (RPE), and choroidal blood vessels. His team was able to see in detail the extent to which choroideremia disrupts these tissues, providing information that could help design effective treatments for this and other diseases. The retina’s RPE is a layer of pigmented cells essential to the nourishment and survival of photoreceptors.
Choroideremia affects men more than women because the gene responsible for the disease is located on the X chromosome. Since men have only one copy of the X chromosome, a mutation in the gene causes males to develop more severe symptoms, while females — who have two copies of the X chromosome — usually have milder symptoms, having one working copy of the gene on the other X chromosome.
“One major finding of our study was that the RPE cells are dramatically enlarged in males and females with choroideremia,” said Tam. “We were surprised to see many cells enlarged by as much as five-fold.”
RPE cells (see circled examples) in a male participant with choroideremia, showing that enlarged RPE cells can be detected using Dr. Tam’s multimodal imaging approach.
