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.
Redesigned MRI holds promise for the diagnosis and treatment of diseases
National Institutes of Health researchers, along with researchers at Siemens, have developed a high-performance, low magnetic-field MRI system that vastly improves image quality of the lungs and other internal structures of the human body. The new system is more compatible with interventional devices that could greatly enhance image-guided procedures that diagnose and treat disease, and the system makes medical imaging more affordable and accessible for patients.
The low-field MRI system may also be safer for patients with pacemakers or defibrillators, quieter, and easier to maintain and install. The study, funded by the National Heart, Lung, and Blood Institute (NHLBI), part of the National Institutes of Health, appears today in the journal Radiology.
The trend in recent years has been to develop MRI systems with higher magnetic field strengths to produce clearer images of the brain. But, researchers calculated that using those same state-of-the-art systems — at a modified strength — might offer high quality imaging of the heart and lungs. They found that metal devices such as interventional cardiology tools that were once at risk of heating with the high-field system were now safe for real-time, image-guided procedures such as heart catherization.
“We continue to explore how MRI can be optimized for diagnostic and therapeutic applications,” said Robert Balaban, Ph.D., scientific director of the Division of Intramural Research and chief of the Laboratory of Cardiac Energetics at NHLBI. “The system reduces the risk of heating — a major barrier to the use of MRI-guided therapeutic approaches that have hampered the imaging field for decades.”
Lung cysts and surrounding tissues in a patient with lymphangioleiomyomatosis (LAM) seen more clearly using high-performance low field MRI compared to standard MRI. Photo credit: Campbell-Washburn A E, Ramasawmy R, Restivo M C, et al. Used by permission.
Pregnant women who are exposed to higher air pollution levels during their second pregnancy, compared to their first one, may be at greater risk of preterm birth, according to researchers at the National Institutes of Health. Their study appears in the International Journal of Environmental Research and Public Health.
Preterm birth, or the birth of a baby before 37 weeks, is one of the leading causes of infant mortality in the United States, according to the Centers for Disease Control and Prevention. Although previous studies have found an association between air pollution exposure and preterm birth risk, the authors believe their study is the first to link this risk to changes in exposure levels between a first and second pregnancy.
“What surprised us was that among low-risk women, including women who had not delivered preterm before, the risk during the second pregnancy increased significantly when air pollution stayed high or increased,” said Pauline Mendola, Ph.D., the study’s lead author and a senior investigator in the Epidemiology Branch at the Eunice Kennedy Shriver National Institute of Child Health and Human Development.
Two-pronged approach stymies AML escape plan, could have applications to many cancers
Scientists from the National Institutes of Health and Cincinnati Children’s Hospital Medical Center have devised a potential treatment against a common type of leukemia that could have implications for many other types of cancer. The new approach takes aim at a way that cancer cells evade the effects of drugs, a process called adaptive resistance.
The researchers, in a range of studies, identified a cellular pathway that allows a form of acute myeloid leukemia (AML), a deadly blood and bone marrow cancer, to elude the activity of a promising class of drugs. They then engineered a compound that appears to launch a two-pronged attack against the cancer. In several experiments, the compound blocked a mutant protein that causes the AML. At the same time, it halted the cancer cells’ ability to sidestep the compound’s effects. The results, reported Sept. 4 in Science Translational Medicine, could lead to the development of new therapies against AML and cancers that act in similar ways.
Co-corresponding authors Daniel Starczynowski, Ph.D., at Cincinnati Children’s, Craig Thomas, Ph.D., at NIH’s National Center for Advancing Translational Sciences (NCATS) and their colleagues wanted to better understand drug resistance in a form of AML caused by a mutant protein called FLT3. This form of AML accounts for roughly 25% of all newly diagnosed AML cases, and patients often have a poor prognosis. A more thorough understanding of the drug resistance process could help them find ways to improve therapy options.
The chemical structure of a prospective drug sitting inside the protein kinase IRAK4.
IRP findings suggest how immune system evolved to withstand food scarcity
Even when taking in fewer calories and nutrients, humans and other mammals usually remain protected against infectious diseases they have already encountered. This may be because memory T cells, which are located throughout the body and required to maintain immune responses to infectious agents, according to scientists at the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health. Their study in mice, published online today in Cell, also found that animals undergoing dietary restriction were better protected against tumors and bacterial infections than animals with unrestricted diets.
Researchers led by Yasmine Belkaid, Ph.D., chief of the Metaorganism Immunity Section in NIAID’s Division of Intramural Research, previously observed that fat tissue harbors memory T cells in mice. They investigated whether this phenomenon helped preserve immune memory when calorie intake was reduced. To investigate, they restricted the diet of mice previously given full access to food. While receiving less food, mice had fewer memory T cells in their lymphoid tissues, where they normally linger, and more of the T cells in bone marrow that became enriched with fat tissue.
Investigators then evaluated how well memory T cells performed when mice ate less. While eating freely, mice were infected with the bacterium Yersinia pseudotuberculosis. After the mice developed immunological memory, researchers restricted the diets of some of the mice for up to four weeks before again exposing all the mice to Y. pseudotuberculosis. Mice with restricted diets had more robust memory T cell responses and were better protected from illness. The researchers repeated this experiment using a vaccine that trains immune cells to fight melanomas and found that memory T cells were more protective against tumors in mice receiving less food.
Colorized scanning electron micrograph of a T cell.
Researchers believe that stuttering — a potentially lifelong and debilitating speech disorder — stems from problems with the circuits in the brain that control speech, but precisely how and where these problems occur is unknown. Using a mouse model of stuttering, scientists report that a loss of cells in the brain called astrocytes are associated with stuttering. The mice had been engineered with a human gene mutation previously linked to stuttering. The study, which appeared online in the Proceedings of the National Academy of Sciences, offers insights into the neurological deficits associated with stuttering.
The loss of astrocytes, a supporting cell in the brain, was most prominent in the corpus callosum, a part of the brain that bridges the two hemispheres. Previous imaging studies have identified differences in the brains of people who stutter compared to those who do not. Furthermore, some of these studies in people have revealed structural and functional problems in the same brain region as the new mouse study.
“The identification of genetic, molecular, and cellular changes that underlie stuttering has led us to understand persistent stuttering as a brain disorder,” said Andrew Griffith, M.D., Ph.D., NIDCD scientific director. “Perhaps even more importantly, pinpointing the brain region and cells that are involved opens opportunities for novel interventions for stuttering — and possibly other speech disorders.”
In a mouse model of stuttering (lower panel), there are fewer astrocytes, shown in green, compared to controls (upper panel) in the corpus callosum, the area of the brain that enables the left and right hemispheres to communicate.
IRP study provides hope for diagnosing and testing effectiveness of new treatments for more disabling forms of multiple sclerosis
Aided by a high-powered brain scanner and a 3D printer, NIH researchers peered inside the brains of hundreds of multiple sclerosis patients and found that dark rimmed spots representing ongoing, “smoldering” inflammation, called chronic active lesions, may be a hallmark of more aggressive and disabling forms of the disease.
“We found that it is possible to use brain scans to detect which patients are highly susceptible to the more aggressive forms of multiple sclerosis. The more chronic active lesions a patient has the greater the chances they will experience this type of MS,” said Daniel S. Reich, M.D., Ph.D., senior investigator at the NIH’s National Institute of Neurological Disorders and Stroke and the senior author of the paper published in JAMA Neurology. “We hope these results will help test the effectiveness of new therapies for this form of MS and reduce the suffering patients experience.”
Affecting more than 2 million people worldwide, multiple sclerosis is a disease for which there is no cure. The disease starts when the immune system attacks myelin, a protective coating that forms around nerve cells in a person’s brain and spinal cord, to produce a variety of initial symptoms, including blurred or double vision, problems with muscle strength, balance and coordination, and abnormal sensations. Treatment with anti-inflammatory medications designed to quiet the immune system has helped some patients fully or partially recover. Nevertheless, a significant subset of patients will eventually suffer from a longer lasting, progressive form of the disease, which can cause further problems including paralysis, loss of bladder control and problems with attention, thinking, and memory.
NIH researchers found that dark rimmed spots representing ongoing, “smoldering” inflammation, may be a hallmark of more disabling forms of multiple sclerosis.
A team of researchers from the National Library of Medicine (NLM), part of the National Institutes of Health, and collaborating academic research institutions developed a method to measure a type of gene mutation involved in the evolution of cancer. This type of mutation, called “repeat instability,” may be useful in early cancer diagnosis. Findings were published this week in the Proceedings of the National Academy of Sciences.
Cancer is primarily caused by mutations in certain genes. The most thoroughly studied cancer-associated mutations involve the substitution of one nucleotide of DNA for another in genes known as oncogenes and tumor suppressors.
In this study, the researchers identified a different type of mutation active in cancer, one that increases and/or decreases repetitive segments of DNA and protein sequences in various genes. These changes are collectively named “repeat instability.”
IRP researchers create mouse colony to address shortcomings of laboratory mice
Researchers at the National Institutes of Health developed a new mouse model that could improve the translation of research in mice into advances in human health. The mouse model, which the scientists called “wildling,” acquired the microbes and pathogens of wild mice, while maintaining the laboratory mice’s genetics that make them more useful for research. In two preclinical studies, wildlings mirrored human immune responses, where lab mice failed to do so. Led by scientists at the NIH’s National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the study published online in Science.
“We wanted to create a mouse model that better resembles a mouse you’d find in the wild,” said Barbara Rehermann, M.D., chief of the Immunology Section in NIDDK’s Liver Diseases Branch and senior author on the study. “Our rationale was that the immune responses and microbiota of wild mice and humans are likely shaped in a similar way — through contact with diverse microbes out in the real world.”
Microbiota refers to the trillions of tiny microbes, such as bacteria, fungi, and viruses, that live in and on the bodies of people and animals and play a critical role in keeping immune systems healthy. Unlike squeaky clean lab mice raised in artificial settings, wild mice have developed symbiotic relationships with microbes they have encountered in the outside world — just as people have done.
Structure-based candidate designed by IRP scientists
A novel experimental vaccine against respiratory syncytial virus (RSV), a leading cause of severe respiratory illness in the very young and the old, has shown early promise in a Phase 1 clinical trial. The candidate, DS-Cav1, was engineered and developed by researchers at the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, who were guided by their atomic-level understanding of the shape of an RSV protein. An interim analysis of study data showed that one dose of the investigational vaccine prompted large increases in RSV-neutralizing antibodies that were sustained for several months. The findings are reported in Science.
First described in 1956 as a cause of infant pneumonia, the health burden of RSV has long been underappreciated. In fact, the virus is an important contributor to serious illness worldwide and causes as many as 118,000 deaths annually among young children. In the United States each year, RSV infections account for approximately 57,000 hospitalizations and 2 million outpatient clinic visits among children younger than 5-years-old, according to the Centers for Disease Control and Prevention. Among people older than 65, RSV is estimated to cause 14,000 annual deaths in the United States. Globally, a recent large study led by the International Vaccine Access Center found that the virus was responsible for 31% of all cases of severe pneumonia requiring hospitalization in young children in seven low- and middle-income countries.
“A vaccine to prevent RSV is a long-sought goal that has eluded us for decades,” said NIAID Director Anthony S. Fauci, M.D. “The early results of this trial suggest that this structure-based strategy for developing an RSV vaccine may bring that goal within reach.”
Scanning electron micrograph of human respiratory syncytial virus (RSV) virions (colorized blue) and labeled with anti-RSV F protein/gold antibodies (colorized yellow) shedding from the surface of human lung epithelial A549 cells.
Scientists using an experimental treatment have slowed the progression of scrapie, a degenerative central nervous disease caused by prions, in laboratory mice and greatly extended the rodents’ lives, according to a new report in JCI Insight. The scientists used antisense oligonucleotides (ASOs), synthetic compounds that inhibit the formation of specific proteins.
Prion diseases occur when normally harmless prion protein molecules become abnormal and gather in clusters and filaments in the body, including the brain. The diseases are thought to be always fatal. Scrapie, which affects sheep and goats and can be adapted to rodents, is closely related to human prion diseases such as Creutzfeldt-Jakob disease, which is currently untreatable. Thus, scrapie is a valuable experimental model for the development of human prion disease therapies.
In the studies, National Institutes of Health scientists and their colleagues injected ASOs into the spinal fluid of mice already infected with scrapie or that were challenged with scrapie proteins within weeks of the injection. Ionis Pharmaceuticals specifically designed ASO1 and ASO2 to reduce the rodents’ supply of normal prion protein. Rodent studies using different dosages of ASO1 and ASO2 were conducted at Rocky Mountain Laboratories (RML) in Hamilton, Montana, (part of the NIH’s National Institute of Allergy and Infectious Diseases) and at the Broad Institute of Cambridge, Massachusetts.
Prion protein, shown in red, can become infectious and cause neurodegenerative disease. Here four nerve cells in a mouse illustrate how infectious prion protein moves within cells along neurites — wire-like connections the nerve cells use for communicating with adjacent cells.
