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.
Researchers at the National Institutes of Health have developed a breath test that measures how well patients with methylmalonic acidemia (MMA) respond to receiving liver or combined liver and kidney transplantation. Researchers also used the test to assess the severity of the disease in people and help determine if they would benefit from surgical or experimental genomic therapies that target the liver. The study results were published in Genetics in Medicine. Scientists at the National Human Genome Research Institute (NHGRI) led the project team, with collaborators from the National Institute of Diabetes and Digestive and Kidney Diseases and the National Institute of Mental Health.
MMA is a rare genomic disease that impairs the body’s ability to metabolize certain proteins and fats. This causes toxic substances to build up, which may result in kidney disease, pancreatitis, movement disorders, intellectual impairments, complications in many organs, and, in severe cases, death. One in 80,000 children born in the United States are diagnosed with MMA during newborn screenings. Currently, MMA is incurable, but people with MMA manage their symptoms through dietary restrictions and vitamin supplements. In extreme cases, patients receive liver or combined liver and kidney transplants, which help restore normal levels of metabolic proteins.
“Vast fluctuations in metabolic substances in the bodies of patients make it difficult for us to tell if treatments like genome editing and transplants are likely to be successful,” said Charles P. Venditti, M.D., Ph.D., senior author and senior investigator in the NHGRI Medical Genomics and Metabolic Genetics Branch. “Instead of looking at levels, we decided to measure metabolism itself.”
Breath test for methylmalonic acidemia measures disease severity and success of liver transplantation for patients.
When variants of SARS-CoV-2 (the virus that causes COVID-19) emerged in late 2020, concern arose that they might elude protective immune responses generated by prior infection or vaccination, potentially making re-infection more likely or vaccination less effective. To investigate this possibility, researchers from the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, and colleagues analyzed blood cell samples from 30 people who had contracted and recovered from COVID-19 prior to the emergence of virus variants. They found that one key player in the immune response to SARS-CoV-2 — the CD8+ T cell — remained active against the virus.
The research team was led by NIAID’s Andrew Redd, Ph.D., and included scientists from Johns Hopkins University School of Medicine, Johns Hopkins Bloomberg School of Public Health, and the Immunomics-focused company, ImmunoScape.
The investigators asked whether CD8+ T cells in the blood of recovered COVID-19 patients, infected with the initial virus, could still recognize three SARS-CoV-2 variants: B.1.1.7, which was first detected in the United Kingdom; B.1.351, originally found in the Republic of South Africa; and B.1.1.248, first seen in Brazil. Each variant has mutations throughout the virus, and, in particular, in the region of the virus’ spike protein that it uses to attach to and enter cells. Mutations in this spike protein region could make it less recognizable to T cells and neutralizing antibodies, which are made by the immune system’s B cells following infection or vaccination.
Scanning electron micrograph of a human T lymphocyte (also called a T cell) from the immune system of a healthy donor.
A new study shows that in the time after first trying cannabis or first misusing prescription drugs, the percentages of young people who develop the corresponding substance use disorder are higher among adolescents (ages 12-17) than young adults (ages 18-25). In addition, 30 percent of young adults develop a heroin use disorder and 25 percent develop a methamphetamine use disorder a year after first using heroin or methamphetamine. These findings, published in JAMA Pediatrics, emphasize the vulnerability of young people to developing substance use disorders.
“We know that young people are more vulnerable to developing substance use disorders, but knowledge is limited on how the prevalence of specific substance use disorders varies by time since first substance use or misuse among adolescents and young adults in the United States,” said Dr. Nora Volkow, M.D., NIDA Director and a lead author of the analysis. “Though not everyone who uses a drug will develop addiction, adolescents may develop addiction to substances faster than young adults. This study provides further evidence that delaying substance exposure until the brain is more fully developed may lower risk for developing a substance use disorder.”
Researchers at the National Institutes of Health (NIH) have discovered specific regions within the DNA of neurons that accumulate a certain type of damage (called single-strand breaks or SSBs). This accumulation of SSBs appears to be unique to neurons, and it challenges what is generally understood about the cause of DNA damage and its potential implications in neurodegenerative diseases.
Because neurons require considerable amounts of oxygen to function properly, they are exposed to high levels of free radicals — toxic compounds that can damage DNA within cells. Normally, this damage occurs randomly. However, in this study, damage within neurons was often found within specific regions of DNA called “enhancers” that control the activity of nearby genes.
Fully mature cells like neurons do not need all of their genes to be active at any one time. One way that cells can control gene activity involves the presence or absence of a chemical tag called a methyl group on a specific building block of DNA. Closer inspection of the neurons revealed that a significant number of SSBs occurred when methyl groups were removed, which typically makes that gene available to be activated.
Neurons (labeled in purple) show signs of an active DNA repair process (labeled in yellow). The cells’ DNA itself is labeled in cyan (in this image, overlap between cyan and yellow appears green).
In a study of mice, treatment with the engineered cells shrank tumors and prevented the cancer from spreading to other parts of the body
Scientists have genetically engineered immune cells, called myeloid cells, to precisely deliver an anticancer signal to organs where cancer may spread. In a study of mice, treatment with the engineered cells shrank tumors and prevented the cancer from spreading to other parts of the body. The study, led by scientists at the National Cancer Institute’s (NCI) Center for Cancer Research, part of the National Institutes of Health, was published March 24, 2021, in Cell.
“This is a novel approach to immunotherapy that appears to have promise as a potential treatment for metastatic cancer,” said the study’s leader, Rosandra Kaplan, M.D., of NCI’s Center for Cancer Research.
Metastatic cancer — cancer that has spread from its original location to other parts of the body — is notoriously difficult to treat. Dr. Kaplan’s team has been exploring another approach: Preventing cancer from spreading in the first place.
Pregnant women who consumed the caffeine equivalent of as little as half a cup of coffee a day on average had slightly smaller babies than pregnant women who did not consume caffeinated beverages, according to a study by researchers at the National Institutes of Health. The researchers found corresponding reductions in size and lean body mass for infants whose mothers consumed below the 200 milligrams of caffeine per day — about two cups of coffee — believed to increase risks to the fetus. Smaller birth size can place infants at higher risk of obesity, heart disease and diabetes later in life.
“Until we learn more, our results suggest it might be prudent to limit or forego caffeine-containing beverages during pregnancy,” Dr. Grantz said. “It’s also a good idea for women to consult their physicians about caffeine consumption during pregnancy.”
NIH-funded findings point to a role for saliva in SARS-CoV-2 transmission
An international team of scientists has found evidence that SARS-CoV-2, the virus that causes COVID-19, infects cells in the mouth. While it’s well known that the upper airways and lungs are primary sites of SARS-CoV-2 infection, there are clues the virus can infect cells in other parts of the body, such as the digestive system, blood vessels, kidneys and, as this new study shows, the mouth. The potential of the virus to infect multiple areas of the body might help explain the wide-ranging symptoms experienced by COVID-19 patients, including oral symptoms such as taste loss, dry mouth and blistering. Moreover, the findings point to the possibility that the mouth plays a role in transmitting SARS-CoV-2 to the lungs or digestive system via saliva laden with virus from infected oral cells. A better understanding of the mouth’s involvement could inform strategies to reduce viral transmission within and outside the body. The team was led by researchers at the National Institutes of Health and the University of North Carolina at Chapel Hill.
“Due to NIH’s all-hands-on-deck response to the pandemic, researchers at the National Institute of Dental and Craniofacial Research were able to quickly pivot and apply their expertise in oral biology and medicine to answering key questions about COVID-19,” said NIDCR Director Rena D’Souza, D.D.S., M.S., Ph.D. “The power of this approach is exemplified by the efforts of this scientific team, who identified a likely role for the mouth in SARS-CoV-2 infection and transmission, a finding that adds to knowledge critical for combatting this disease.”
The study, published online March 25, 2021 in Nature Medicine, was led by Blake M. Warner, D.D.S., Ph.D., M.P.H., assistant clinical investigator and chief of NIDCR’s Salivary Disorders Unit, and Kevin M. Byrd, D.D.S., Ph.D., at the time an assistant professor in the Adams School of Dentistry at the University of North Carolina at Chapel Hill. Byrd is now an Anthony R. Volpe Research Scholar at the American Dental Association Science and Research Institute. Ni Huang, Ph.D., of the Wellcome Sanger Institute in Cambridge, U.K., and Paola Perez, Ph.D., of NIDCR, were co-first authors.
RNA for SARS-CoV-2 (pink) and the ACE2 receptor (white) was found in salivary gland cells, which are outlined in green.
By eliminating extraneous light, the scientists improved resolution by 33 percent
A team led by scientists at the National Eye Institute (NEI) has noninvasively visualized the light-sensing cells in the back of the eye, known as photoreceptors, in greater detail than ever before. Published in Optica, the researchers report how they improved imaging resolution by a third by selectively blocking the light used to image the eye. NEI is part of the National Institutes of Health.
The achievement is the latest in an evolving strategy to monitor cell changes in retinal tissue that, in turn, will help identify new ways to treat and prevent vision loss from diseases such as age-related macular degeneration, a leading cause of blindness in people age 65 and older.
“Better imaging resolution will enable better tracking of degenerative changes that occur in retinal tissue. The goal of our research is to discern disease-related changes at the cellular level over time, possibly enabling much earlier detection of disease,” said the study’s lead investigator, Johnny Tam, Ph.D., Stadtman Investigator in the Clinical and Translational Imaging Unit at NEI.
The mosaic of cone and rod photoreceptor cells is shown by confocal imaging (left) and split detection.
Novel research in mice sheds light on hormone regulation needed in late pregnancy, opens door for therapy
New research by the National Institutes of Health found that unbalanced progesterone signals may cause some pregnant women to experience preterm labor or prolonged labor. The study in mice — published online in the Proceedings of the National Academy of Sciences — provides novel insights for developing treatments.
During pregnancy, the hormone progesterone helps to prevent the uterus from contracting and going into labor prematurely. This occurs through molecular signaling involving progesterone receptor types A and B, referred to as PGR-A and PGR-B. In this first-of-its-kind study, the scientists showed how unbalanced PGR-A and PGR-B signaling can affect pregnancy duration.
“We used genetically engineered mouse models to alter the ratio of PGR-A and PGR-B in the muscle compartment of the uterus, called the myometrium,” said senior author Francesco DeMayo, Ph.D., head of the National Institute of Environmental Health Sciences Reproductive and Developmental Biology Laboratory. “Our team found that PGR-A promotes muscle contraction and PGR-B prevents such contraction, and we identified the biological pathways influenced by both forms.”
The mosquito protein AEG12 strongly inhibits the family of viruses that cause yellow fever, dengue, West Nile, and Zika and weakly inhibits coronaviruses, according to scientists at the National Institutes of Health (NIH) and their collaborators. The researchers found that AEG12 works by destabilizing the viral envelope, breaking its protective covering. Although the protein does not affect viruses that do not have an envelope, such as those that cause pink eye and bladder infections, the findings could lead to therapeutics against viruses that affect millions of people around the world. The research was published online in PNAS.
Scientists at the National Institute of Environmental Health Sciences (NIEHS), part of NIH, used X-ray crystallography to solve the structure of AEG12. Senior author Geoffrey Mueller, Ph.D., head of the NIEHS Nuclear Magnetic Resonance Group, said at the molecular level, AEG12 rips out the lipids, or the fat-like portions of the membrane that hold the virus together.
"It is as if AEG12 is hungry for the lipids that are in the virus membrane, so it gets rid of some of the lipids it has and exchanges them for the ones it really prefers," Mueller said. "The protein has high affinity for viral lipids and steals them from the virus."
Bite by an Aedes mosquito. This species can transmit diseases such as chikungunya, dengue, and Zika.
