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:
BETHESDA, Md. (AP) — Sam Srisatta, a 20-year-old Florida college student, spent a month living inside a government hospital here last fall, playing video games and allowing scientists to document every morsel of food that went into his mouth.
From big bowls of salad to platters of meatballs and spaghetti sauce, Srisatta noshed his way through a nutrition study aimed at understanding the health effects of ultraprocessed foods, the controversial fare that now accounts for more than 70% of the U.S. food supply. He allowed The Associated Press to tag along for a day.
“Today my lunch was chicken nuggets, some chips, some ketchup,” said Srisatta, one of three dozen participants paid $5,000 each to devote 28 days of their lives to science. “It was pretty fulfilling.”
Examining exactly what made those nuggets so satisfying is the goal of the widely anticipated research led by National Institutes of Health nutrition researcher Kevin Hall.
“What we hope to do is figure out what those mechanisms are so that we can better understand that process,” Hall said.
An independent data and safety monitoring board (DSMB) overseeing the Phase 3 trial of the investigational COVID-19 vaccine known as mRNA-1273 reviewed trial data and shared its interim analysis with the trial oversight group on Nov. 15, 2020. This interim review of the data suggests that the vaccine is safe and effective at preventing symptomatic COVID-19 in adults. The interim analysis comprised 95 cases of symptomatic COVID-19 among volunteers. The DSMB reported that the candidate was safe and well-tolerated and noted a vaccine efficacy rate of 94.5 percent. The findings are statistically significant, meaning they are likely not due to chance. Ninety of the cases occurred in the placebo group and five occurred in the vaccinated group. There were 11 cases of severe COVID-19 out of the 95 total, all of which occurred in the placebo group.
The mRNA-1273 vaccine candidate 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. It combines Moderna’s mRNA (messenger RNA) delivery platform with the stabilized SARS-CoV-2 spike immunogen (S-2P) developed by NIAID scientists.
The vaccine candidate transitioned from early development with NIAID to the Biomedical Advanced Research and Development Authority (BARDA), part of the Department of Health and Human Services Office of the Assistant Secretary for Preparedness and Response, for advanced development and manufacturing support, to meet the federal government’s Operation Warp Speed (OWS) goals.
3D print of a spike protein of SARS-CoV-2, the virus that causes COVID-19, in front of a 3D print of a SARS-CoV-2 virus particle. The spike protein (foreground) enables the virus to enter and infect human cells. On the virus model, the virus surface (blue) is covered with spike proteins (red) that enable the virus to enter and infect human cells.
National Institutes of Health researchers have discovered a gene in mice that controls the craving for fatty and sugary foods and the desire to exercise. The gene, Prkar2a, is highly expressed in the habenula, a tiny brain region involved in responses to pain, stress, anxiety, sleep and reward. The findings could inform future research to prevent obesity and its accompanying risks for cardiovascular disease and diabetes. The study was conducted by Edra London, Ph.D., a staff scientist in the section on endocrinology and genetics at NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), and colleagues. It appears in JCI Insight.
Prkar2a contains the information needed to make two subunits — molecular components — of the enzyme protein kinase A. Enzymes speed up chemical reactions, either helping to combine smaller molecules into larger molecules, or to break down larger molecules into smaller ones. Protein kinase A is the central enzyme that speeds reactions inside cells in many species. In a previous study, the NICHD team found that despite being fed a high fat diet, mice lacking functioning copies of Prkar2a were less likely to become obese than wild type mice with normally functioning Prkar2a.
The researchers determined that Prkar2a-negative mice ate less high-fat food than their counterparts, not only when given unlimited access to the food, but also after a fast. Similarly, the Prkar2a-negative mice also drank less of a sugar solution than the wild type mice. The Prkar2a-negative mice were also more inclined to exercise, running two to three times longer than wild type mice on a treadmill. Female Prkar2a-negative mice were less inclined to consume high fat foods than Prkar2-negative males, while Prkar2-negative males showed less preference for the sugar solution than Prkar2-negative females.
Gut-trained immune cells at CNS borders guard against meningitis and other infections
The membranes surrounding our brains are in a never-ending battle against deadly infections, as germs constantly try to elude watchful immune cells and sneak past a special protective barrier called the meninges. In a study involving mice and human autopsy tissue, researchers at the National Institutes of Health and Cambridge University have shown that some of these immune cells are trained to fight these infections by first spending time in the gut.
“This finding opens a new area of neuroimmunology, showing that gut-educated antibody-producing cells inhabit and defend regions that surround the central nervous system,” said Dorian McGavern, Ph.D., senior investigator at NINDS and co-senior author of the study, which was published in Nature.
The central nervous system (CNS) is protected from pathogens both by a three-membrane barrier called the meninges and by immune cells within those membranes. The CNS is also walled off from the rest of the body by specialized blood vessels that are tightly sealed by the blood brain barrier. This is not the case, however, in the dura mater, the outermost layer of the meninges. Blood vessels in this compartment are not sealed, and large venous structures, referred to as the sinuses, carry slow moving blood back to the heart. The combination of slow blood flow and proximity to the brain requires strong immune protection to stop potential infections in their tracks.
Targeting cells’ ‘trash compactor’ could lead to new antiviral strategy to fight COVID-19
Researchers at the National Institutes of Health have discovered a biological pathway that the novel coronavirus appears to use to hijack and exit cells as it spreads through the body. A better understanding of this important pathway may provide vital insight in stopping the transmission of the virus — SARS-CoV-2 — which causes COVID-19 disease.
In cell studies, the researchers showed for the first time that the coronavirus can exit infected cells through the lysosome, an organelle known as the cells’ “trash compactor.” Normally the lysosome destroys viruses and other pathogens before they leave the cells. However, the researchers found that the coronavirus deactivates the lysosome’s disease-fighting machinery, allowing it to freely spread throughout the body.
Targeting this lysosomal pathway could lead to the development of new, more effective antiviral therapies to fight COVID-19. The findings, published today in the journal Cell, come at a time when new coronavirus cases are surging worldwide, with related U.S. deaths nearing 225,000.
Illustration shows components of the lysosome exocytosis pathway, which coronaviruses use to exit cells. Also shown are components of the normal biosynthetic secretory pathway. Image credit: NIH Medical Arts
NIH study suggests women with mood disorders, gestational diabetes may have a higher risk
A National Institutes of Health study of 5,000 women has found that approximately 1 in 4 experienced high levels of depressive symptoms at some point in the three years after giving birth. The rest of the women experienced low levels of depression throughout the three-year span. The study was conducted by researchers at NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). It appears in the journal Pediatrics.
The American Academy of Pediatrics recommends that pediatricians screen mothers for postpartum depression at well-child visits at one, two, four and six months after childbirth. Researchers identified four trajectories of postpartum depressive symptoms and the factors that may increase a woman’s risk for elevated symptoms. The findings suggest that extending screening for postpartum depressive symptoms for at least two years after childbirth may be beneficial, the authors write.
“Our study indicates that six months may not be long enough to gauge depressive symptoms,” said Diane Putnick, Ph.D., the primary author and a staff scientist in the NICHD Epidemiology Branch. “These long-term data are key to improving our understanding of mom’s mental health, which we know is critical to her child’s well-being and development.”
Researchers from the National Institutes of Health (NIH) have discovered a new inflammatory disorder called vacuoles, E1 enzyme, X-linked, autoinflammatory and somatic syndrome (VEXAS), which is caused by mutations in the UBA1 gene. VEXAS causes symptoms that included blood clots in veins, recurrent fevers, pulmonary abnormalities and vacuoles (unusual cavity-like structures) in myeloid cells. The scientists reported their findings in the New England Journal of Medicine.
Nearly 125 million people in the U.S. live with some form of a chronic inflammatory disease. Many of these diseases have overlapping symptoms, which often make it difficult for researchers to diagnose the specific inflammatory disease in a given patient.
Researchers at the National Human Genome Research Institute (NHGRI), part of the NIH, and collaborators from other NIH Institutes took a unique approach to address this challenge. They studied the genome sequences from more than 2,500 individuals with undiagnosed inflammatory diseases, paying particular attention to a set of over 800 genes related to the process of ubiquitylation, which helps regulate both various protein functions inside a cell and the immune system overall. By doing so, they found a gene that is intricately linked to VEXAS, a disease which can be life-threatening. So far, 40 percent of VEXAS patients who the team studied have died, revealing the devastating consequences of the severe condition.
Researchers from NIH have discovered a new inflammatory disorder called vacuoles, E1 enzyme, X-linked, autoinflammatory and somatic syndrome (VEXAS), which is caused by mutations in the UBA1 gene. Image by Harry Wedel, NHGRI.
The plant compound apigenin improved the cognitive and memory deficits usually seen in a mouse model of Down syndrome, according to a study by researchers at the National Institutes of Health and other institutions. Apigenin is found in chamomile flowers, parsley, celery, peppermint and citrus fruits. The researchers fed the compound to pregnant mice carrying fetuses with Down syndrome characteristics and then to the animals after they were born and as they matured. The findings raise the possibility that a treatment to lessen the cognitive deficits seen in Down syndrome could one day be offered to pregnant women whose fetuses have been diagnosed with Down syndrome through prenatal testing. The study appears in the American Journal of Human Genetics.
Down syndrome is a set of symptoms resulting from an extra copy or piece of chromosome 21. The intellectual and developmental disabilities accompanying the condition are believed to result from decreased brain growth caused by increased inflammation in the fetal brain. Apigenin is not known to have any toxic effects, and previous studies have indicated that it is an antioxidant that reduces inflammation. Unlike many compounds, it is absorbed through the placenta and the blood brain barrier, the cellular layer that prevents potentially harmful substances from entering the brain. Compared to mice with Down symptoms whose mothers were not fed apigenin, those exposed to the compound showed improvements in tests of developmental milestones and had improvements in spatial and olfactory memory. Tests of gene activity and protein levels showed the apigenin-treated mice had less inflammation and increased blood vessel and nervous system growth.
In a National Institutes of Health-funded study involving both mice and patients who are part of an NIH Clinical Center trial, researchers discovered that a gene, called PIEZO2, may be responsible for the powerful urge to urinate that we normally feel several times a day. The results, published in Nature, suggest that the gene helps at least two different types of cells in the body sense when our bladders are full and need to be emptied. These results also expand the growing list of newly discovered senses under the gene’s control.
Urine is produced when the kidneys extract waste and excess water from the blood and send it to the bladder. Over time, it fills up and expands like a balloon, putting tension on the bladder muscles. Then, at a certain point, the body senses that it is reaching a limit, which triggers the urge to urinate.
The PIEZO2 gene contains instructions for making proteins that are activated when cells are stretched or squeezed. In this study, the researchers found that patients who are born with a genetic deficiency in PIEZO2 have trouble sensing bladder filling while experiments in mice suggested the gene plays two critical roles in this process. It may help certain bladder cells gauge expansion while also sparking neurons to relay tension signals to the rest of the nervous system.
Researchers discovered that a gene called PIEZO2 may help us sense when our bladders are full, and it is time to urinate. Above is an example of a mouse bladder used in the study.
As genome-editing trials become more common, informed consent is changing
As public interest and expanded research in human genome editing grows, many questions remain about ethical, legal and social implications of the technology. People who are seriously ill may overestimate the benefits of early clinical trials while underestimating the risks. This makes properly understanding informed consent, the full knowledge of risks and benefits of treatments, especially important.
In response to this emerging need, researchers at the National Human Genome Research Institute (NHGRI), part of the National Institutes of Health, asked patients, parents and physicians in the sickle cell disease community what they wanted and needed to know about genome editing to make informed decisions about participating in genome-editing clinical trials. Gene-editing treatments, which appear to provide a potential for sickle cell, are among the most widely publicized medical advances in recent years. The results were published this week in the journal AJOB Empirical Bioethics.
“An important goal of informed consent is to facilitate decisions that are consistent with a person’s values,” said Sara Hull, Ph.D., director of the Bioethics Core at NHGRI. “By talking to sickle cell disease stakeholders ahead of time, we can learn more about their values and hopefully do a better job of pinpointing what kinds of information will be most useful to potential research participants as they make very a difficult decision.”
Results suggest retrieval of cellular powerplants via an energy feedback loop sustains communication
Our thoughts, feelings, and movements are controlled by billions of neurons talking to each other at trillions of specialized communication points called synapses. In an in-depth study of neurons grown in laboratory petri dishes, National Institutes of Health researchers discovered how the chattiest of some synapses find the energy to support intense conversations thought to underlie learning and memory. Their results, published in Nature Metabolism, suggest that a series of chemical reactions control a feedback loop that senses the need for more energy and replenishes it by recruiting cellular powerplants, called mitochondria, to the synapses. The experiments were performed by researchers in a lab led by Zu-Hang Sheng, Ph.D., at the NIH’s National Institute of Neurological Disorders and Stroke (NINDS).
The team studied synapses that use the neurotransmitter glutamate to communicate. Communication happens when a packet of glutamate is released from presynaptic boutons which are tiny protrusions that stick out, like beads on a string, of long, wiry parts of neurons called axons. Previously, Dr. Sheng’s team showed that synaptic communication is an energy-demanding process and that mitochondria traveling along axons can control signals sent by boutons. Boutons that had mitochondria sent stronger and more consistent signals than those that were missing powerplants. The difference was due to higher energy levels produced by the mitochondria in the form of ATP.
In this study, led by Sunan Li, Ph.D., a post-doctoral fellow at NINDS, the team investigated what happens when boutons undergo intense communication thought to underlie learning and memory. They found that this type of signaling quickly dropped energy levels at boutons. These changes triggered a series of chemical reactions controlled by an energy sensor called AMP-activated protein kinases (AMPK) that ultimately led to the rapid recruitment of mitochondria to the boutons. Genetically blocking or chemically interfering with this feedback loop prevented the delivery of mitochondria to boutons and lowered energy levels. This, in turn, reduced synaptic responses during intense communication more than seen in control cells and slowed the recovery of the responses after the bursts ended. The researchers concluded that this feedback loop may normally play a critical role in providing the energy needed to sustain synaptic communication throughout a healthy nervous system. For example, they cite studies which implied that problems with this system may occur in some cases of Alzheimer’s disease and other neurological disorders.
Intense neural conversations thought to underlie learning and memory may be fueled by an energy-sensing feedback loop. Scientist monitored energy levels in the form of ATP as neurons talked to each other.
