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.
Two doses of an experimental vaccine to prevent coronavirus disease 2019 (COVID-19) induced robust immune responses and rapidly controlled the coronavirus in the upper and lower airways of rhesus macaques exposed to SARS-CoV-2, report scientists from the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health. SARS-CoV-2 is the virus that causes COVID-19.
The candidate vaccine, mRNA-1273, was co-developed by scientists at the NIAID Vaccine Research Center and at Moderna, Inc., Cambridge, Massachusetts. The animal study results published online today in the New England Journal of Medicine complement recently reported interim results from an NIAID-sponsored Phase 1 clinical trial of mRNA-1273. The candidate mRNA-1273 vaccine is manufactured by Moderna.
In this study, three groups of eight rhesus macaques received two injections of 10 or 100 micrograms (µg) of mRNA-1273 or a placebo. Injections were spaced 28 days apart. Vaccinated macaques produced high levels of neutralizing antibodies directed at the surface spike protein used by SARS-CoV-2 to attach to and enter cells. Notably, say the investigators, animals receiving the 10-µg or 100-µg dose vaccine candidate produced neutralizing antibodies in the blood at levels well above those found in people who recovered from COVID-19.
Colorized scanning electron micrograph of a cell (blue) heavily infected with SARS-CoV-2 virus particles (red), isolated from a patient sample.
A new study, which analyzed 40 years of Framingham Heart Study data, found an association between lowered rates of hip fractures and decreases in smoking and heavy drinking.The rates of hip fractures in the United States have been declining over the past few decades. Although some experts attribute this change primarily to improved treatments for bone health, a new National Institutes of Health-supported study suggests other factors. These results indicate that modifiable lifestyle factors, along with treatments, may be beneficial to bone health. The findings appear July 27, 2020 in JAMA Internal Medicine.
The analysis included information from 4,918 men and 5,634 women who participated in the Framingham Study. These individuals were followed for a first hip fracture between Jan. 1, 1970, and Dec. 31, 2010. The rates for hip fractures, which were adjusted for age, dropped by 4.4% each year across the 40-year study period. The decrease was seen in both men and women.
Multi-site trial to test candidate developed by Moderna and NIH
A Phase 3 clinical trial designed to evaluate if an investigational vaccine can prevent symptomatic coronavirus disease 2019 (COVID-19) in adults has begun. The vaccine, known as mRNA-1273, was co-developed by the Cambridge, Massachusetts-based biotechnology company Moderna, Inc., and the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health. The trial, which will be conducted at U.S. clinical research sites, is expected to enroll approximately 30,000 adult volunteers who do not have COVID-19.
“Although face coverings, physical distancing and proper isolation and quarantine of infected individuals and contacts can help us mitigate SARS-CoV-2 spread, we urgently need a safe and effective preventive vaccine to ultimately control this pandemic,” said NIAID Director Anthony S. Fauci, M.D. “Results from early-stage clinical testing indicate the investigational mRNA-1273 vaccine is safe and immunogenic, supporting the initiation of a Phase 3 clinical trial. This scientifically rigorous, randomized, placebo-controlled trial is designed to determine if the vaccine can prevent COVID-19 and for how long such protection may last.”
Moderna is leading the trial as the regulatory sponsor and is providing the investigational vaccine for the trial. The Biomedical Advanced Research and Development Authority (BARDA) of the U.S. Department of Health and Human Services’ Office of the Assistant Secretary for Preparedness and Response and NIAID are providing funding support for the trial. The vaccine efficacy trial is the first to be implemented under Operation Warp Speed, a multi-agency collaboration led by HHS that aims to accelerate the development, manufacturing and distribution of medical countermeasures for COVID-19.
National Institutes of Health Director Francis S. Collins, M.D., Ph.D., has chosen Michael F. Chiang, M.D., as director of NIH’s National Eye Institute (NEI). A practicing ophthalmologist, Dr. Chiang is currently the Knowles Professor of Ophthalmology & Medical Informatics and Clinical Epidemiology at Oregon Health & Science University (OHSU), Portland, and is associate director of the OHSU Casey Eye Institute. He is expected to begin his new role as the NEI director in late 2020. NEI conducts and supports research and training into blinding eye diseases, visual disorders, mechanisms of visual function, preservation of sight and the special health problems and requirements of the visually impaired.
“Dr. Chiang brings extensive experience as a clinician, researcher and educator to NIH. His work in biomedical informatics and telehealth research are particularly important for the future of vision research,” said Dr. Collins. “I look forward to having him join the NIH leadership team later this year. I also want to recognize Santa J. Tumminia, Ph.D., for her dedicated leadership in serving as the acting director of NEI since October 2019.”
As director, Dr. Chiang will oversee NEI’s annual budget of nearly $824 million, the large majority of which supports vision research through approximately 1,600 research grants and training awards made to scientists at more than 250 medical centers, universities and other institutions across the country and around the world. NEI research leads to sight-saving treatments, reduces visual impairment and blindness and improves the quality of life for people of all ages. The institute also conducts laboratory and patient-oriented research at its own facilities on the NIH campus in Bethesda, Maryland.
IL-17, known for driving inflammation, also puts on the brakes, NIH scientists report
The inflammatory molecule interleukin-17A (IL-17A) triggers immune cells that in turn reduce IL-17A’s pro-inflammatory activity, according to a study by National Eye Institute (NEI) researchers. In models of autoimmune diseases of the eye and brain, blocking IL-17A increased the presence of other inflammatory molecules produced by Th17 cells, immune cells that produce IL-17A and are involved in neuroinflammation. The finding could explain why IL-17-targeted treatments for conditions like the eye disease autoimmune uveitis and multiple sclerosis (MS) have failed. A report on the findings was published in Immunity. NEI is part of the National Institutes of Health.
In autoimmune uveitis, immune cells become abnormally activated and begin to destroy healthy cells, including light-sensing photoreceptors and neurons. A key immune cell involved in this response is the Th17 lymphocyte, which produces several pro-inflammatory molecules known as cytokines. A hallmark of Th17 cells is the ability to produce IL-17A, which attracts immune cells called neutrophils that can damage tissue. Nevertheless, multiple clinical trials of drugs that block IL-17A have failed to help people with autoimmune uveitis or MS.
“IL-17 is the prototypical inflammatory immune molecule blamed for autoimmunity in the neuro-retina and the brain, but there’s been some controversy about the role it plays,” said Rachel Caspi, Ph.D., chief of the Laboratory of Immunology at NEI and senior author of the study. “In our model of autoimmune uveitis, we noticed that without IL-17, the amount of tissue damage unexpectedly stayed the same and we had higher levels of other inflammatory molecules.”
After activation through its T-cell receptor, Th17 cells produce IL-17A, which binds to its own receptor on the Th17 cell. This activates the NFκB pathway. NFκB drives production of IL-24, which in turn suppresses the Th17 cytokine program via SOCS1 and 3.
Gene expression data suggest potential role of sex chromosomes
A scientific analysis of more than 2,000 brain scans found evidence for highly reproducible sex differences in the volume of certain regions in the human brain. This pattern of sex-based differences in brain volume corresponds with patterns of sex-chromosome gene expression observed in postmortem samples from the brain’s cortex, suggesting that sex chromosomes may play a role in the development or maintenance of sex differences in brain anatomy. The study, led by researchers at the National Institute of Mental Health (NIMH), part of the National Institutes of Health, is published in Proceedings of the National Academy of Sciences.
“Developing a clearer understanding of sex differences in human brain organization has great importance for how we think about well-established sex differences in cognition, behavior, and risk for psychiatric illness. We were inspired by new findings on sex differences in animal models and wanted to try to close the gap between these animal data and our models of sex differences in the human brain,” said Armin Raznahan, M.D., Ph.D., study co-author and chief of the NIMH Section on Developmental Neurogenomics.
Researchers have long observed consistent sex-based differences in subcortical brain structures in mice. Some studies have suggested these anatomical differences are largely due to the effects of sex hormones, lending weight to a “gonad-centric” explanation for sex-based differences in brain development. However, more recent mouse studies have revealed consistent sex differences in cortical structures, as well, and gene-expression data suggest that sex chromosomes may play a role in shaping these anatomical sex differences. Although the mouse brain shares many similarities with the human brain, it is not clear whether these key findings in mice also apply to humans.
The accomplishment opens a new era in genomics research
Researchers at the National Human Genome Research Institute (NHGRI), part of the National Institutes of Health, have produced the first end-to-end DNA sequence of a human chromosome. The results, published today in Nature, show that generating a precise, base-by-base sequence of a human chromosome is now possible, and will enable researchers to produce a complete sequence of the human genome.
Humans have two sets of chromosomes, one set from each parent. For example, biologically female humans inherit two X chromosomes, one from their mother and one from their father. However, those two X chromosomes are not identical and will contain many differences in their DNA sequences.
In this study, researchers did not sequence the X chromosome from a normal human cell. Instead, they used a special cell type – one that has two identical X chromosomes. Such a cell provides more DNA for sequencing than a male cell, which has only a single copy of an X chromosome. It also avoids sequence differences encountered when analyzing two X chromosomes of a typical female cell.
NIH study may help explain why the virus has rarely been found in fetuses or newborns of women with COVID-19
The placental membranes that contain the fetus and amniotic fluid lack the messenger RNA (mRNA) molecule required to manufacture the ACE2 receptor, the main cell surface receptor used by the SARS-CoV-2 virus to cause infection, according to a study by researchers at the National Institutes of Health. Their findings appear in the journal eLife.
These placental tissues also lack mRNA needed to make an enzyme, called TMPRSS2, that SARS-CoV-2 uses to enter a cell. Both the receptor and enzyme are present in only miniscule amounts in the placenta, suggesting a possible explanation for why SARS-CoV-2 has only rarely been found in fetuses or newborns of women infected with the virus, according to the study authors.
The researchers, led by Roberto Romero, M.D., chief of the Perinatology Research Branch at NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), found that the placenta contains molecules that previous studies have suggested as potential routes for SARS-CoV-2 infection, including the CD147 receptor and the enzymes cathepsin L and Furin. They also detected in placental and membrane tissue a type of macrophage (immune cell) that has the ACE2 receptor. However, they noted that there is little evidence showing that infected macrophages could spread the SARS-CoV-2 virus to the placenta, membranes and fetus in normal pregnancy.
For every cell in the body there comes a time when it must decide what it wants to do for the rest of its life. In an article published in the journal PNAS, National Institutes of Health researchers report for the first time that ancient viral genes that were once considered “junk DNA” may play a role in this process. The article describes a series of preclinical experiments that showed how some human endogenous retrovirus (HERV-K) genes inscribed into chromosomes 12 and 19 may help control the differentiation, or maturation, of human stem cells into the trillions of neurons that are wired into our nervous systems. The experiments were performed by researchers in a lab led by Avindra Nath, M.D., clinical director, at the NIH’s National Institute of Neurological Disorders and Stroke (NINDS).
Over the course of evolution, the human genome has absorbed thousands of human endogenous retrovirus genes. As a result, nearly eight percent of the DNA that lines our chromosomes includes remnants of these genes. Although once thought to be inactive, or “junk”, recent studies have shown that these genes may be involved in human embryonic development, the growth of some tumors, and nerve damage during multiple sclerosis. Previously, researchers in Dr. Nath’s lab showed that amyotrophic lateral sclerosis (ALS) may be linked to activation of the HERV-K gene. In this study, led by Tongguang (David) Wang, M.D., Ph.D., staff scientist at NINDS, the team showed that deactivation of the gene may free stem cells to become neurons.
Comparing epigenetic differences between humans and domestic dogs provides an emerging model of aging
One of the most common misconceptions is that one human year equals seven dog years in terms of aging. However, this equivalency is misleading and has been consistently dismissed by veterinarians. A recent study, published in the journal Cell Systems, lays out a new framework for comparing dog-to-human aging. In one such comparison, the researchers found the first eight weeks of a dog’s life is comparable to the first nine months of human infancy, but the ratio changes over time. The research used epigenetics, a process by which modifications occur in the genome, as a biological marker to study the aging process. By comparing when and what epigenetic changes mark certain developmental periods in humans and dogs, researchers hope to gain specific insight into human aging as well.
Researchers performed a comprehensive analysis and quantitatively compared the progression of aging between two mammals, dogs and humans. Scientists at the National Human Genome Research Institute (NHGRI), part of the National Institutes of Health, and collaborators at the University of California (UC) San Diego, UC Davis and the University of Pittsburgh School of Medicine carried out the research.
All mammals experience the same overarching developmental timeline: birth, infancy, youth, puberty, adulthood and death. But researchers have long sought specific biological events that govern when such life stages take place. One means to study such a progression involves epigenetics — gene expression changes caused by factors other than the DNA sequence itself. Recent findings have shown that epigenetic changes are linked to specific stages of aging and that these are shared among species.
