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 study suggests our brains use distinct firing patterns to store and replay memories
In a study of epilepsy patients, researchers at the National Institutes of Health monitored the electrical activity of thousands of individual brain cells, called neurons, as patients took memory tests. They found that the firing patterns of the cells that occurred when patients learned a word pair were replayed fractions of a second before they successfully remembered the pair. The study was part of an NIH Clinical Center trial for patients with drug-resistant epilepsy whose seizures cannot be controlled with drugs.
“Memory plays a crucial role in our lives. Just as musical notes are recorded as grooves on a record, it appears that our brains store memories in neural firing patterns that can be replayed over and over again,” said Kareem Zaghloul, M.D., Ph.D., a neurosurgeon-researcher at the NIH’s National Institute of Neurological Disorders and Stroke (NINDS) and senior author of the study published in Science.
Dr. Zaghloul’s team has been recording electrical currents of drug-resistant epilepsy patients temporarily living with surgically implanted electrodes designed to monitor brain activity in the hopes of identifying the source of a patient’s seizures. This period also provides an opportunity to study neural activity during memory. In this study, his team examined the activity used to store memories of our past experiences, which scientists call episodic memories.
IRP researchers found that our brains may store memories in neuronal firing patterns that are replayed fractions of a second before remembering.
Researchers at the National Institutes of Health and the University of Wisconsin have demonstrated that using artificial intelligence to analyze CT scans can produce more accurate risk assessment for major cardiovascular events than current, standard methods such as the Framingham risk score (FRS) and body-mass index (BMI).
More than 80 million body CT scans are performed every year in the U.S. alone, but valuable prognostic information on body composition is typically overlooked. In this study, for example, abdominal scans done for routine colorectal cancer screening revealed important information about heart-related risks – when AI was used to analyze the images.
The study compared the ability of automated CT-based body composition biomarkers derived from image-processing algorithms to predict major cardiovascular events and overall survival against routinely used clinical parameters. The investigators found that the CT-based measures were more accurate than FRS and BMI in predicting downstream adverse events including death or myocardial infarction, cerebrovascular accident, or congestive heart failure. The results appeared in The Lancet Digital Health.
“We found that automated measures provided more accurate risk assessments than established clinical biomarkers,” said Ronald M. Summers, M.D., Ph.D., of the NIH Clinical Center and senior author of the study. “This demonstrates the potential of an approach that uses AI to tap into the biometric data embedded in all such scans performed for a wide range of other indications and derive information that can help people better understand their overall health and risks of serious adverse events.”
Improved diagnosis could reduce the risk of both overtreatment and undertreatment of the disease
A method of testing for prostate cancer developed at the National Cancer Institute (NCI) leads to more accurate diagnosis and prediction of the course of the disease, according to a large study. This method, which combines systematic biopsy, the current primary diagnostic approach, with MRI-targeted biopsy, is poised to greatly improve prostate cancer diagnosis, thereby reducing the risk of both overtreatment and undertreatment of the disease. NCI is part of the National Institutes of Health.
The findings were published March 5, 2020, in the New England Journal of Medicine. The study was conducted at the NIH Clinical Center in Bethesda, Maryland.
“Prostate cancer has been one of the only solid tumors diagnosed by performing systematic biopsies ‘blind’ to the cancer’s location. For decades this has led to the overdiagnosis and subsequent unnecessary treatment of non-lethal cancers, as well as to missing aggressive high-grade cancers and their opportunity for cure,” said Peter Pinto, M.D., of the Urologic Oncology Branch in NCI’s Center for Cancer Research and senior author of the study. “With the addition of MRI-targeted biopsy to systematic biopsy, we can now identify the most lethal cancers within the prostate earlier, providing patients the potential for better treatment before the cancers spread.”
A 3-D map of the prostate using combined MRI-targeted and systematic biopsies. Using both types of biopsy greatly improved prostate cancer diagnosis in a new study.
NIH-funded project in mice provides insights into why nerves fail to regrow following injury
When the spinal cord is injured, the damaged nerve fibers — called axons — are normally incapable of regrowth, leading to permanent loss of function. Considerable research has been done to find ways to promote the regeneration of axons following injury. Results of a study performed in mice and published in Cell Metabolism suggests that increasing energy supply within these injured spinal cord nerves could help promote axon regrowth and restore some motor functions. The study was a collaboration between the National Institutes of Health and the Indiana University School of Medicine in Indianapolis.
“We are the first to show that spinal cord injury results in an energy crisis that is intrinsically linked to the limited ability of damaged axons to regenerate,” said Zu-Hang Sheng, Ph.D., senior principal investigator at the NIH’s National Institute of Neurological Disorders and Stroke (NINDS) and a co-senior author of the study.
Like gasoline for a car engine, the cells of the body use a chemical compound called adenosine triphosphate (ATP) for fuel. Much of this ATP is made by cellular power plants called mitochondria. In spinal cord nerves, mitochondria can be found along the axons. When axons are injured, the nearby mitochondria are often damaged as well, impairing ATP production in injured nerves.
“Nerve repair requires a significant amount of energy,” said Dr. Sheng. “Our hypothesis is that damage to mitochondria following injury severely limits the available ATP, and this energy crisis is what prevents the regrowth and repair of injured axons.”
After injury (see damage at the center of the image), nerve fibers (in red) regrow past the injury (right) when energy levels in the tissue are increased.
Findings suggest drugs targeting immune cells may help treat deadly disease mainly affecting children
Researchers at the National Institutes of Health found evidence that specific immune cells may play a key role in the devastating effects of cerebral malaria, a severe form of malaria that mainly affects young children. The results, published in the Journal of Clinical Investigation, suggest that drugs targeting T cells may be effective in treating the disease. The study was supported by the NIH Intramural Research Program.
“This is the first study showing that T cells target blood vessels in brains of children with cerebral malaria,” said Dorian McGavern, Ph.D., chief of the Viral Immunology and Intravital Imaging Section at the NIH’s National Institute of Neurological Disorders and Stroke (NINDS) who co-directed the study with Susan Pierce, Ph.D., chief of the Laboratory of Immunogenetics at the National Institute of Allergy and Infectious Diseases (NIAID). “These findings build a bridge between mouse and human cerebral malaria studies by implicating T cells in the development of disease pathology in children. It is well established that T cells cause the brain vasculature injury associated with cerebral malaria in mice, but this was not known in humans.”
More than 200 million people worldwide are infected annually with mosquito-borne parasites that cause malaria. In a subset of those patients, mainly young children, the parasites accumulate in brain blood vessels causing cerebral malaria, which leads to increased brain pressure from swelling. Even with available treatment, cerebral malaria still kills up to 25% of those affected resulting in nearly 400,000 deaths annually. Children who survive the infection will often have long-lasting neurological problems such as cognitive impairment.
Specific immune cells accumulate within brain blood vessels of people affected by cerebral malaria. This finding suggests a new treatment strategy for the disease.
Women who go on to develop type 2 diabetes after having gestational, or pregnancy-related, diabetes are more likely to have particular genetic profiles, suggests an analysis by researchers at the National Institutes of Health and other institutions. The findings provide insight into the genetic factors underlying the risk of type 2 diabetes and may inform strategies for reducing this risk among women who had gestational diabetes.
“Our study suggests that a healthful diet may reduce risk among women who have had gestational diabetes and are genetically susceptible to type 2 diabetes,” said the study’s senior author Cuilin Zhang, M.D., Ph.D., of NICHD’s Division of Intramural Population Health Research. “However, larger studies are needed to validate these findings.”
Results support testing antiviral against 2019 novel coronavirus
The experimental antiviral remdesivir successfully prevented disease in rhesus macaques infected with Middle East respiratory syndrome coronavirus (MERS-CoV), according to a new study from National Institutes of Health scientists. Remdesivir prevented disease when administered before infection and improved the condition of macaques when given after the animals already were infected.
MERS-CoV is closely related to the 2019 novel coronavirus (2019-nCoV) that has grown to be a global public health emergency since cases were first detected in Wuhan, China, in December.
Colorized scanning electron micrograph of Middle East Respiratory Syndrome virus particles attached to the surface of an infected cell.
NIH-supported research of Hydractinia could provide clues to human reproductive conditions
A little-known ocean-dwelling creature most commonly found growing on dead hermit crab shells may sound like an unlikely study subject for researchers, but this animal has a rare ability — it can make eggs and sperm for the duration of its lifetime. This animal, called Hydractinia, does so because it produces germ cells, which are precursors to eggs and sperm, nonstop throughout its life. Studying this unique ability could provide insight into the development of human reproductive system and the formation of reproductive-based conditions and diseases in humans.
“By sequencing and studying the genomes of simpler organisms that are easier to manipulate in the lab, we have been able to tease out important insights regarding the biology underlying germ cell fate determination — knowledge that may ultimately help us better understand the processes underlying reproductive disorders in humans,” said Dr. Andy Baxevanis, director of the National Human Genome Research Institute’s (NHGRI) Computational Genomics Unit and co-author of the paper. NHGRI is part of the National Institutes of Health.
In a study published in the journal Science, collaborators at NHGRI, the National University of Ireland, Galway, and the Whitney Laboratory for Marine Bioscience at the University of Florida, Augustine, reported that activation of the gene Tfap2 in adult stem cells in Hydractinia can turn those cells into germ cells in a cycle that can repeat endlessly.
Timing of germ cell formation in Hydractinia versus most animals. Image credit: NHGRI
Gene modifications correspond to blood pressure increases at distinct pregnancy intervals
Higher maternal blood pressure in pregnancy is associated with chemical modifications to placental genes, according to a study by researchers from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), part of the National Institutes of Health (NIH). The changes involve DNA methylation, the binding of compounds known as methyl groups to DNA, which can alter a gene’s activity. Exposure to high blood pressure in the womb increases the risk for impaired fetal growth and the risk for cardiovascular disease in adult life. Ultimately, the findings could yield information on the earliest origins of cardiovascular disease and how to prevent it from occurring.
The researchers conducted a comprehensive genetic analysis, called an epigenome-wide association study (EWAS), on biopsies of placentas delivered from 301 pregnant women in the NICHD Fetal Growth Study. EWAS detects DNA methylation and other changes to gene functioning. The authors believe their study is the first EWAS to compare placental DNA methylation to maternal blood pressure across trimesters. The study team found distinct patterns of DNA methylation in the placental tissue, which corresponded with the timing of blood pressure elevations in pregnancy. Many of the methylated genes were found in earlier studies to be involved in cardiovascular functioning.
The researchers hope to study patterns of DNA methylation in larger groups of pregnant women, including those with pregnancy-associated blood pressure disorders such as preeclampsia.
A Phase 1 clinical trial testing the safety and effectiveness of a monoclonal antibody (mAb) against malaria has begun enrolling healthy adult volunteers at the National Institutes of Health Clinical Center in Bethesda, Maryland. The trial, sponsored by NIH’s National Institute of Allergy and Infectious Diseases (NIAID), is the first to test mAb CIS43LS in humans. It aims to enroll up to 73 volunteers aged 18 through 50 years old who have never had malaria. After receiving mAb CIS43LS, most of the volunteers will be exposed to malaria parasite-carrying mosquitoes under carefully controlled conditions at the Walter Reed National Military Medical Center in Bethesda to assess the ability of the mAb to confer protection from malaria infection.
“If proven safe and effective in this study and in larger trials, this monoclonal antibody might be used prophylactically by tourists, medical workers or military personnel who travel to areas where malaria is common,” said NIAID Director Anthony S. Fauci, M.D. “In the absence of a highly effective, long-lasting vaccine, preventing malaria infections for several months with a single dose of monoclonal antibody also could be valuable in specific parts of Africa where malaria cases increase greatly during annual rainy seasons,” he added.
Several years ago, Robert Seder, M.D., and colleagues at NIAID’s Vaccine Research Center (VRC) isolated an antibody (CIS43) from the blood of a volunteer who had received an investigational vaccine made from whole, weakened malaria parasites. When tested in two different mouse models of malaria infection, CIS43 was highly effective at preventing infection by the deadliest malaria parasite, Plasmodium falciparum, the team reported in 2018. Modifications to CIS43 yielded mAb CIS43LS, which lasts longer in the blood than the original antibody. CIS43LS was manufactured for clinical use by the VRC’s investigational product Vaccine Production Program and the NIAID-funded Vaccine Clinical Material Program of Leidos Biomedical Research, Inc., under a contract to the National Cancer Institute’s Frederick National Laboratory for Cancer Research.
NIAID Research Nurse Jennifer Cunningham, B.S.N., looks on as a healthy volunteer receives an infusion of CIS43LS, an experimental monoclonal antibody against malaria, as part of a Phase 1 clinical trial.
