Posted on NIH. 8 October, 2020
The National Institutes of Health (NIH) is our nation’s medical research agency and strives to make scientific discoveries that improve health and save lives. Founded in 1870, the NIH conducts its own scientific research through its Intramural Research Program (IRP), which supports approximately 1,200 principal investigators and more than 4,000 postdoctoral fellows conducting basic, translational and clinical research. In this blog, we will highlight recent ground-breaking NIH research.
The National Institutes of Health has recently announced that they will be awarding $129.3 million in funding to nine companies in support of scaling-up coronavirus testing and manufacturing new testing technologies.
The funding is part of NIH’s Rapid Acceleration of Diagnostics (RADx) initiative to speed up innovation in the development, commercialization, and implementation of technologies for COVID-19 testing. Key focus areas for the new COVID-19 testing technologies are on portable point-of-care tests that allow for immediate results and high-throughput laboratories that can return results within 24 hours.
“Diagnostic testing is a critical component of the nation’s strategy to meet the challenge of the COVID-19 pandemic,” said NIH Director Francis Collins, M.D., Ph.D. “Just started at the end of April, the RADx initiative has moved swiftly to speed innovation and later-stage development in the biomedical technology sector. The results thus far have been outstanding.”
The contracts that are currently in progress include several new technologies, some that utilize a real-time polymerase chain reaction (RT-PCR), which is a highly sensitive method for qualitatively detecting nucleic acid from SARS-CoV-2. Included is a portable, battery-powered RT-PCR device that provides accurate results within 15 minutes, and a portable mini-lab with reagent flexibility that can perform RT-PCR assays in community hospitals and clinics in underserved, rural populations. Other new technologies include a lateral-flow immunoassay test strip that can be read without specialized equipment (similar to home pregnancy tests) and a sample concentrating method that greatly improves the sensitivity and performance of many different types of tests. The development of these new testing capabilities enable significant expansion of COVID-19 screening on a nationwide level.
“Many of these tests incorporate innovations that have moved from research labs to the point of care with unprecedented speed,” said Dr. Bruce Tromberg, director of the National Institute of Biomedical Imaging and Bioengineering and lead for RADx Tech. “That process normally takes years, but RADx has brought together key experts in technology, medicine and commercialization to bring new tests to market in only five to six months.”
The following companies have achieved key RADx milestones and will receive support for scale up and manufacturing efforts:
COVID-19 Point-of-care tests:
COVID-19 Lab-based testing:
The rapid worldwide spread and impact of the COVID-19 pandemic has created a need for accurate, reliable, and readily accessible testing on an unprecedented scale. The safe return to normal life critically depends on the ability to streamline and speed up the testing process. The opportunity to accelerate the development, advancement and scale-up of innovative COVID-19 testing technologies provided by NIH and RADx will make a significant contribution to this global effort.
Maintaining a healthy body weight has never been more challenging than during the recent COVID-19 pandemic with many disruptions to our normal routines. More than 40 percent of American adults are obese, which has long been associated with the incidence of diabetes and heart disease. The consumption of large amounts of energy-rich, foods that are often high in fat, such as fast food and desserts is a contributing factor to obesity. Eating healthier alternatives can lead to weight loss and improved health, but maintaining a healthy diet is easier said than done.
In a recent study, IRP researchers have determined that a high-fat diet can dramatically alter how the brain responds to food in ways that make a more nutritious meal less satisfying.
“I think we’ve all had that experience of deciding ‘I’m going to start eating healthy,’ but sticking to that is difficult,” says IRP senior investigator Dr. Michael Krashes. This is a phenomenon that happens in almost everyone.” Dr. Krashes and other neuroscientists have found that a set of neurons, located in the hypothalamus region of the brain, release a molecule called agouti-related peptide (AgRP) that plays a major role in food consumption. These cells are highly active when we are hungry, and are thought to produce the negative feelings associated with hunger. Consuming food calms these neurons, thereby curbing the desire to eat.
In a new IRP study from Dr. Krashes’ team, led Dr. Christopher Mazzone and Jing Liang-Guallpa, they investigated the effect of a high-fat diet on the function of the AgRP neurons. Mice were provided either with a standard laboratory mouse diet or with both the standard diet along with the typical rodent chow that is much higher in fat. The group of mice with access to high-fat food all but completely ignored the standard food and gained substantial amounts of weight. However, when those animals lost access to the high-fat chow, they continued to shun the standard food, consuming so little of it that they actually lost weight. Their aversion to the standard chow remained even when they were forced to fast overnight to boost their appetites. After the fasting period, the mice were observed to consume large amounts of the high-fat food when provided with it.
“Even though the mice are in need of calories and are really hungry, they’ll basically go on a hunger strike and refuse to eat the standard diet for a long period of time,” says Dr. Krashes. “After we’ve given them this high-fat diet, they like it so much that they now don’t want to even touch that other type of food.”
The IRP team also recorded the electrical activity of AgRP neurons in fasted animals. These experiments showed that consumption of standard rodent chow suppressed AgRP neuron activity much less in hungry mice that had previously received high-fat food compared to mice that had not, suggesting that the standard chow did little to satisfy the appetites of the mice. Animals exposed to the high-fat diet shunned the standard chow even when Dr. Krashes’ team boosted their drive to eat by directly stimulating their AgRP neurons. However, this direct stimulation successfully increased consumption of the standard chow in animals that had never been on a high-fat diet.
These findings, along with changes in several other brain areas that the IRP scientists observed in mice given high-fat food, suggest a neurological explanation for why it is so difficult to maintain a healthy diet. Plans for future studies by Dr. Krashes’ team include the investigation of how a high-fat diet changes the behavior of genes in different populations of brain cells in mice. This next stage of research could identify specific therapeutic drug targets and inform solutions that help people make long-term changes to their eating habits.
Respiratory viruses such as the flu have widely varying effects on different patients from mild or asymptomatic to potentially life-threatening consequences from the disease. A new study by IRP researchers has found that exposure to a common variety of mold primes the immune system to overreact to the flu virus, which can dramatically increase the severity of the illness.
The fungi that make up patches of mold release spores into the air, which are often inhaled by humans and other organisms. In locations with temperate climates, such as the mid-Atlantic United States, one of the most common varieties of mold is Alternaria alternata. Chronic inhalation of fungi has been linked to the development of respiratory ailments such as asthma and inflammation of the lungs.
“The black mold in the basement you see on TV shows where they do home rehabs — that’s Alternaria alternata for the most part,” says IRP senior investigator Dr. Helene Rosenberg. “It’s everywhere, and certain people are extremely sensitive to it.”
In an earlier study, Dr. Rosenberg and her team had found that mice repeatedly exposed to Alternaria alternata had more immune cells called eosinophils in their nasal passages. Even though eosinophils are known to help combat viruses, the mice exposed to the fungus were actually more susceptible to the flu. Surprisingly, the normally protective immune cells were unable to prevent a catastrophic reaction to the flu virus in those animals.
A new study conducted by Dr. Rosenberg’s lab was aimed at discovering why this had occurred. The IRP scientists prepared solutions containing varying amounts of Alternaria alternata and repeatedly introduced them into the nasal passages of mice over a three week period. The animals were then exposed to an amount of flu virus that normally causes a non-lethal illness. The mice exposed to low concentrations of the fungus or a solution containing none of the mold got sick but ultimately recovered, whereas many of the animals exposed to moderate or high doses of Alternaria alternata prior to flu infection died. Mice exposed to the mold but not the virus did not exhibit any signs of illness.
The mice that were exposed to the mold did not have more flu virus particles in their airways than mice without exposure, indicating that increased susceptibility to the flu was not due to elevated replication of the virus in their bodies. However, their lungs exhibited significant inflammation, containing increased levels of certain inflammatory molecules. The fungus-exposed mice also had many more immune cells in their lungs, predominantly immune cells called neutrophils. The results of the study suggest that inhaling Alternaria alternata primes the immune system to respond in a dangerously strong manner to a respiratory virus like the flu.
The study also noted that repeatedly introducing a probiotic bacterium called Lactobacillus plantarum into the mice’s nasal passages along with Alternaria alternata showed a positive outcome following flu infection. Despite having equal numbers of viral particles in their airways, mice that received Lactobacillus lost less weight after flu infection and were more likely to survive than their counterparts that inhaled the mold alone. Additionally, their lungs contained lower levels of inflammatory molecules. This treatment also proved to be beneficial when the Lactobacillus plantarum had been inactivated by heat prior to inoculation.
Dr. Rosenberg’s research highlights the need for clinical studies that examine whether the symptoms of respiratory viruses like the flu are more severe in people who live in regions where mold is more common or who have mold in their homes or workplaces. “Standing next to mold for five minutes may not be a big issue, but if it’s in your ventilation system at home or at work, that may have more profound health implications than we previously thought,” Dr. Rosenberg says. Doctors might begin to closely monitor or more aggressively treating patients who have been exposed to mold, and advise public health officials of the imperative need for the elimination of mold inside of buildings.
Eczema is a chronic inflammatory skin disease characterized by red itchy skin rashes. The disease is most common in children and is linked to an increased risk of developing asthma, hay fever and food allergies. While available treatments can help manage eczema symptoms, current options can be costly, often requiring multiple daily applications.
In a recent study conducted by researchers at the NIH, an experimental therapy for the treatment of eczema was shown to reduce the severity of the disease and improved the quality of life in children as young as 3 years of age. This novel therapy contains strains of live Roseomonas mucosa, a bacterium naturally present on the skin, was isolated from healthy volunteers and grown under carefully controlled laboratory conditions. During a four month clinical trial, participants or their caregivers periodically applied this probiotic therapy to areas of skin affected by eczema. The effectiveness of this therapy lasted for up to eight months post treatment.
“A child suffering from eczema, which can be itchy, painful and distracting for the child, also is very difficult for the entire family,” said Dr. Anthony Fauci, director of NIH’s National Institute of Allergy and Infectious Diseases (NIAID), which led the study. “These early-stage findings suggest that R. mucosa therapy may help relieve some children of both the burden of eczema symptoms and the need for daily treatment.”
NIAID launched a Phase 1/2 clinical trial at the NIH Clinical Center in Bethesda, Maryland, to assess the safety and potential benefit of R. mucosa therapy in people with eczema. Interim results reported in 2018 for 10 adults and five children aged 9 to 14 years indicated that the treatment was safe and reduced the severity of eczema. The trial has now enrolled a total of 20 children with mild to severe eczema ranging in age from 3 to 16 years.
Of the 20 children enrolled in the study, 17 have experienced more than 50% improvement in the severity of eczema following treatment. Improvement occurred on all treated skin sites, including the inner elbows, inner knees, hands, trunk and neck. The scientists also noted an improvement in the barrier function of the skin, sealing in moisture and keeping out allergens. The majority of the children who participated in the study required fewer corticosteroids to manage their eczema, experienced less itching, and reported a better quality of life following the therapy. The R. mucosa bacteria was shown to remain on the skin for up to eight months, allowing the benefit of the therapy to continue for that period of time post treatment.
In subsequent studies, NIAID researchers found that treated skin had increased microbial diversity and reduced levels of Staphylococcus aureus, a bacterium known to exacerbate eczema. In addition to overall imbalances in the microbiome, the skin of people with eczema is deficient in certain lipids, or oils. By conducting experiments in cell and animal models of eczema, the researchers found that a specific set of lipids produced by R. mucosa strains isolated from healthy skin can induce skin repair processes and promote turnover of skin tissue. Study participants had increased levels of these lipids on their skin after treatment with R. mucosa.
The NIAID research team emphasizes that additional studies are required to further elucidate the mechanism of R. mucosa therapy and to explore whether genetic or other factors may explain why some participants did not benefit from the experimental treatment.
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a serious, long-term illness with many adverse effects. People with ME/CFS are often not able to do their usual daily activities and may even confine them to bed. Other symptoms can include severe fatigue, difficulty concentrating, pain, dizziness and sleep disturbances. ME/CFS may get worse after physical or mental exertion, resulting in what is known as post-exertional malaise (PEM). There currently are no treatment options for patients with ME/CFS.
In a study published in Frontiers in Neurology, people with ME/CFS described the extensive debilitating effects of PEM. “Post-exertional malaise following normal activities is unique to ME/CFS and we do not understand the biology underlying this severe and harmful feature of the disease,” said Dr. Walter Koroshetz, director of NIH’s National Institute of Neurological Disorders and Stroke (NINDS). “In-depth conversations with people who experienced post-exertional malaise and listening to them describe their individual experiences can provide a perspective not achieved through surveys. This study provides a window into just how much post-exertional malaise can affect a person’s quality of life.”
The research team led by Dr. Avindra Nath, clinical director of NINDS, recruited 43 individuals with ME/CFS to participate in nine focus groups discussing their experiences with post-exertional malaise, including activities that led up to the onset of the condition, the duration period, and the techniques they used to help decrease their symptoms. Five out of the nine focus groups included participants who experienced PEM following a cardiopulmonary exercise test (CPET), which is a measurement of how the body responds to exercise and is generally conducted using a stationary bike.
Qualitative analysis from the focus groups revealed that although the participants used a wide range of phrases to describe their experiences, many of their PEM symptoms fell into three primary categories: exhaustion, cognitive difficulties, and neuromuscular complaints. Additional PEM symptoms included headaches, pain, nausea, sore throat, and sensitivity to light and sound. The onset of PEM is generally between 24 and 48 hours after exertion and can last from 24 hours to several weeks.
The study also identified the differences between PEM caused by daily activities, such as grocery shopping or going to a doctor’s appointment, and PEM caused by the lab test CPET. The results suggest that the overall symptoms were similar, but PEM caused by the exercise test came on faster and lasted longer. The majority of the study participants indicated that complete rest, often in a dark and quiet room, was required to help reduce the symptoms of PEM. Many participants would plan ahead to limit activities in an effort to decrease the onset of PEM, while also acknowledging that it can occur unexpectedly.
Additional research is needed to gain a more thorough understand of the causes of PEM in people with ME/CFS. Future studies focused upon the identification of the sub-types of PEM may help guide targeted treatments to improve the quality of life for those affected by this debilitating disease.
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