Posted on NIH. 3 February, 2021
The National Institutes of Health (NIH) is our nation’s medical research agency. It’s mission focuses on scientific discoveries that improve health and save lives. Founded in 1870, the NIH research 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 innovative NIH research.
A new genetic disorder named LINKED was recently discovered by researchers at the National Institute of Health (NIH). Linkage-specific-deubiquitylation-deficiency-induced embryonic defects syndrome (LINKED) is characterized by developmental delays and malformations of the brain, heart and facial features. The cause of this syndrome is due to mutations in the OTUD5 gene, causing interference with key molecular steps in embryo development. Findings from this study indicate that the newly identified pathway may be essential for human development and may also contribute to other disorders that are present at birth.
The project began when Dr. David Beck, a clinical fellow in the laboratory of Dr. Dan Kastner at the National Human Genome Research Institute (NHGRI) and co-first author, was asked to consult on a male infant who had been born with severe birth defects. Abnormalities of the brain, craniofacial skeleton, heart and urinary tract were present in the infant. Following thorough examination of the family members’ genomes, in conjunction with genetic bioinformatics analyses, a mutation in the OTUD5 gene was determined as the likely cause of the condition. Through collaboration with researchers working on related problems, Dr. Beck found that seven additional males ranging from 1 to 14 years of age, who exhibited symptoms similar to the first patient, also had varying mutations in the OTUD5 gene.
“Our discovery of the dysregulated neurodevelopmental pathway that underlies LINKED syndrome was only possible through the teamwork of geneticists, developmental biologists and biochemists from NIH research,” said Dr. Achim Werner, Investigator at National Institute of Dental and Craniofacial Research (NIDCR) and lead author. “This collaboration provided the opportunity to pinpoint the likely genetic cause of disease, and then take it a step further to precisely define the sequence of cellular events that are disrupted to cause the disease.”
The gene contains instructions for making the OTUD5 enzyme, which is involved in ubiquitylation, a process that molecularly alters a protein to change its function. Ubiquitylation plays a role in governing cell fate, where stem cells are instructed to become specific cell types in the early stages of embryo development.
“Based on the genetic evidence, I was pretty sure OTUD5 mutations caused the disease, but I didn’t understand how this enzyme, when mutated, led to the symptoms seen in our patients,” said Dr. Beck. “For this reason, we sought to work with Dr. Werner’s group, which specializes in using biochemistry to understand the functions of enzymes like OTUD5.”
In this study, the NIH research team examined cells taken from patient samples, which were processed at the NIH Clinical Center. Normally, OTUD5 edits or removes molecular tags on certain proteins to regulate their function. However, in cells obtained from patients having the OTUD5 mutations, this activity was impaired. Using a method to return mature human cells to the stem cell-like state of embryo cells, the scientists found that OTUD5 mutations were linked to abnormalities in the development of neural crest cells, giving rise to tissues of the craniofacial skeleton and neural precursors cells that eventually lead to the formation of the brain and spinal cord.
Further experimentation concluded that the OTUD5 enzyme acts on a handful of protein substrates called chromatin remodelers. This class of proteins physically alters the tightly packed strands of DNA in a cell’s nucleus to make certain genes more accessible for being turned on, or expressed. With help from a collaboration team, led by Dr. Pedro Rocha, Investigator at the National Institute of Child Health and Human Development (NICHD), it was discovered that chromatin remodelers targeted by OTUD5 help enhance the expression of genes which control the cell fate of neural precursors during embryo development. OTUD5 normally keeps chromatin remodelers from being tagged for destruction. But when OTUD5 is mutated, its protective function is lost and the chromatin remodelers are destroyed, leading to the abnormal development of neural precursors and neural crest cells. These changes can lead to some of the birth defects that have been observed in LINKED patients.
“Several of the chromatin remodelers OTUD5 interacts with are mutated in Coffin Siris and Cornelia de Lange syndromes, which have clinically overlapping features with LINKED syndrome,” says Dr. Werner. “This suggests that the mechanism we discovered is part of a common developmental pathway that, when mutated at various points, will lead to a spectrum of disease.”
While additional studies are needed to further determine the role that OTUD5 and related enzymes have in development, the researchers hope that the study will serve as a framework for unraveling the causes of other undiagnosed diseases, ultimately helping clinicians to better assess and care for patients.
A recent study, conducted by researchers at the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), compared the effects of a low-fat, plant based diet with that of a low-carbohydrate, animal-based diet and it’s impact on how restricting dietary carbohydrate or fats may impact overall health in humans.
“High-fat foods have been thought to result in excess calorie intake because they have many calories per bite. Alternatively, high-carb foods can cause large swings in blood glucose and insulin that may increase hunger and lead to overeating,” said Dr. Kevin Hall, Senior Investigator at NIDDK and the study’s lead author. “Our study was designed to determine whether high-carb or high-fat diets result in greater calorie intake.”
The researcher team housed 20 adults without diabetes for four continuous weeks in the NIH Clinical Center’s Metabolic Clinical Research Unit. The participants, comprised of 11 men and 9 women, received either a plant-based, low-fat, high carbohydrate diet or an animal-based, low-carbohydrate diet for a period of two weeks, immediately followed by two weeks on the alternate diet. Both diets contained minimally processed food and had equivalent amounts of non-starchy vegetables. The participants were given three meals a day, including snacks, and could eat as much as they desired.
The plant-based, low-fat diet contained 10.3% fat and 75.2% carbohydrate, while the animal-based, low-carb diet was 10% carbohydrate and 75.8% fat. Both diets contained about 14% protein and were matched for total calories presented to the subjects, although the low-carb diet had twice as many calories per gram of food than the low-fat diet. On the low-fat menu, dinner might consist of a baked sweet potato, chickpeas, broccoli and oranges, while a low-carb dinner might be beef stir fry with cauliflower rice. Subjects could eat what and however much they chose of the meals they were given.
The study concluded that the people on the low-fat diet ate 550 to 700 fewer calories per day than when they ate the low-carb diet. Despite the large differences in calorie intake, participants reported no differences in hunger, enjoyment of meals, or fullness between the two diets. Participants lost weight on both diets, but only the low-fat diet led to a significant loss of body fat.
“Despite eating food with an abundance of high glycemic carbohydrates that resulted in pronounced swings in blood glucose and insulin, people eating the plant-based, low-fat diet showed a significant reduction in calorie intake and loss of body fat, which challenges the idea that high-carb diets per se lead people to overeat. On the other hand, the animal-based, low-carb diet did not result in weight gain despite being high in fat,” said Dr. Hall.
The overall findings of this study suggest that the factors that result in overeating and weight gain are more complex than the amount of carbs or fat in one’s diet. In further support of this hypotheses, Dr. Hall’s 2019 study indicated that a diet high in ultra-processed food led to overeating and weight gain in comparison to a diet comprised of minimally processed food, having the equivalent amount of carbs and fat.
“Interestingly, our findings suggest benefits to both diets, at least in the short-term. While the low-fat, plant-based diet helps curb appetite, the animal-based, low-carb diet resulted in lower and more steady insulin and glucose levels,” says Dr. Hall. “We don’t yet know if these differences would be sustained over the long term.”
The researchers note that the study was not designed to make diet recommendations for weight loss. Meals were prepared and provided for the study participants in a controlled clinical environment to ensure the objective measurement of food intake and the accuracy of the resulting data. External factors including whether or not the participants were actively trying to lose weight, the cost and availability of food, and meal preparation constraints may have a further impact of the outcome of the study in a real life setting.
“To help us achieve good nutrition, rigorous science is critical − and of particular importance now, in light of the COVID-19 pandemic, as we aim to identify strategies to help us stay healthy,” said Dr. Griffin Rodgers, NIDDK Director. “This study brings us closer to answering long-sought questions about how what we eat affects our health.”
Researchers from the National Institute of Neurological Disorders and Stroke (NINDS) have discovered a rare new immune cell in the brain with “Jekyll and Hyde” properties that ultimately assist with brain repair, but early after injury can lead to fatal swelling. These dual-purpose cells, called myelomonocytic cells and which are carried to the brain by the blood, are just one type of brain immune cell that researcher team tracked in a real-time of the brain as it repaired itself following injury.
“Timing is of the essence when trying to prevent fatal edema. You want to prevent the acute brain swelling and damage, but you do not want to block the monocytes from their beneficial repair work,” said Dr. McGavern.
Cerebrovascular injury, or damage to brain blood vessels, can occur following several conditions including traumatic brain injury or stroke. In a research study led by NINDS scientists Dr. Dorian McGavern, senior author of the study, and Dr. Larry Latour, it was observed that a subset of stroke patients developed bleeding and swelling in the brain following the surgical removal of the blood vessel clot responsible for the stroke. The swelling, also known as edema, results in poor outcomes and can even be fatal as brain structures become compressed and further damaged.
Dr. McGavern and his team developed an animal model of cerebrovascular injury to study the mechanism by which blood vessel injury can lead to swelling of the brain. Utilizing state-of-the-art microscopic imaging, the research team was able to watch how the brain responded to damage in real-time. Immediately following injury, brain immune cells, known as microglia, quickly mobilize to stop the blood vessels from leaking. These “first responders” of the immune system extend out and wrap their arms around broken blood vessels. Dr. McGavern’s group discovered that removing microglia causes irreparable bleeding and damage within the brain.
Within a few hours, the damaged brain is then invaded by circulating peripheral monocytes and neutrophils (or, myelomonocytic cells). As myelomonocytic cells move from the blood into the brain, they each open a small hole in the vasculature, causing a mist of fluid to enter the brain. When thousands of these cells rush into the brain simultaneously, a lot of fluid comes in all at once, potentially leading to devastating tissue damage and swelling. Should this phenomenon occur near the brain stem, vital functions such as breathing could be negatively impacted.
Following this initial surge, the monocytic subset of immune cells enter the brain at a much slower, less damaging rate and get to work repairing the vessels. Monocytes work together with repair-associated microglia to rebuild the damaged vascular network, which is reconnected within 10 days of injury. The monocytes are required for this important repair process.
In an effort to reduce secondary swelling and tissue damage, the scientists used a combination of therapeutic antibodies that stop myelomonocytic cells from entering the brain. The antibodies blocked two different adhesion molecules that myelomonocytic cells use to attach to inflamed blood vessels. These were effective at reducing brain swelling and improving outcomes when administered within six hours of injury. However, the therapeutic antibodies did not work if given later than six hours or if they were given for too long, resulting in the inhibition of the proper repair of damaged blood vessels, ultimately leading to neuronal death and brain scarring.
Future research studies will examine additional aspects of the cerebrovascular repair process, with the hope of identifying potential treatment strategies to promote reparative immune functions.
The NIH/FDA COVID-19 Research Workshop, October 2020 virtual event showcased research conducted by the NIH and FDA in fight against COVID-19.
The event featured roughly 135 presentations including 56 talks and 79 flash talks representing some 250 labs working on COVID-19 projects. National Institute of Allergy and Infectious Diseases Director, Dr. Anthony Fauci, kicked off the first day with an overview of our current knowledge of SARS-CoV-2 and described therapeutic treatments being tested and vaccine trials taking place. In a similar fashion, NIH Research Director, Dr. Francis Collins, opened the second day by congratulating the researchers presenting their work.
View the Session Summaries Below:
Introduction: Megan Kalomiris, NIAID
October 31st is a date often associated with spooky costumes and eating candy, but it holds additional significance this year—it was the 80th anniversary of President Franklin Delano Roosevelt’s 1940 dedication of the National Institute of Health’s (yes, it was singular back then) Bethesda campus. Roosevelt’s vision for the NIH was to use science to protect the health of the American people, and 80 years later during the midst of the COVID-19 pandemic, the NIH is still doing just that.
Session 1: Tracking, Diagnostics, and Prevention, Frances Fernando, NICHD
Session 2: Virology 1: Replication, Evolution, and Host Factors, Natalie Hagen, NCATS
Session 3: Virology II: Structure, Function, and Inhibition of Viral Proteins, Sunita Chopra, NCI
Session 4: Clinical Manifestations and Pathogenesis, Ethan Smith, NINR
Session 5: Host Response and Immunology, June Guha, NIAID
Session 6: Animal Models and Vaccines, Charlesice Hawkins, OITE
“This was an amazing two-day banquet,” said Deputy Director for Intramural Research Michael Gottesman in his closing remarks at the end of the workshop. He noted that almost all the talks described research that involved collaborations and featured “amazing research talent at NIH.”
Research teams at the National Institute of Allergy and Infectious Diseases (NIAID) in collaboration with the biotech company Moderna, Inc. have been working to develop a safe and effective vaccine in the fight against SARS-CoV-2, the coronavirus that causes COVID-19. Early results from one vaccine candidate, called mRNA-1273, showed it can trigger an immune response against the virus without serious side effects.
To further investigate the safety and efficacy of this vaccine, a research team led by Dr. Lindsey Baden of Brigham and Women’s Hospital in Boston, Dr. Hana El-Sahly of Baylor College of Medicine, and Dr. Brandon Essink of Meridian Clinical Research carried out a clinical trial with more than 30,000 adult volunteers nationwide. Participants were 18 years of age or older with no known previous SARS-CoV-2 infection.
The study volunteers were randomly assigned to receive either two doses of the investigational vaccine or two shots of a saline placebo. They received the first injection between July 27 and October 23, 2020. The second shot was given 28 days after. The research team recorded 196 cases of symptomatic COVID-19 among participants at least 14 days after they received their second shot. Only 11 of these cases were in the group that received the vaccine. None of the recorded cases of COVID-19 were severe. In contrast, 185 of the cases occurred in the placebo group, 30 of which were severe. The incidence of symptomatic COVID-19 was 94.1% lower in participants who received mRNA-1273 compared to those who received the placebo. For participants 65 years or older, the efficacy was 86.4%.
Local reactions to the vaccine were generally mild, with no concerning safety issues reported. About half the participants receiving mRNA-1273 experienced moderate to severe side effects including fatigue, muscle aches, joint pain and headache following the second dose. In most volunteers, these symptoms resolved within a period of two days.
One potential concern surrounding COVID-19 vaccines is an unusual phenomenon called vaccine-associated enhanced respiratory disease, or VAERD. VAERD can occur when a vaccine induces an immune response that causes the disease to be more severe if you’re exposed to the virus. However, the team found no evidence of VAERD among those who received mRNA-1273.
“There is much we still do not know about SARS-CoV-2 and COVID-19. However, we do know that this vaccine is safe and can prevent symptomatic COVID-19 and severe disease,” says NIAID Director, Dr. Anthony Fauci. “It is my hope that all Americans will protect themselves by getting vaccinated when the vaccine becomes available to them. That is how our country will begin to heal and move forward.”
The FDA issued an Emergency Use Authorization for Moderna, making the vaccine available for the prevention of COVID-19 in adults on December 18, 2020. Although mRNA-1273 can prevent symptomatic COVID-19, more research is required to determine whether it protects against SARS-CoV-2 transmission and to understand the vaccine’s impact on asymptomatic infections.
Tuesday, February 9, 2021, 2:00 pm to 3:00 pm
Harmonizing the Spiritual and Scientific Worldviews
Tuesday, February 23, 2021, 8:00 am to Wednesday, February 24, 2021, 4:00 pm (register by Feb 5th)
Impact of Environmental Exposures on the Microbiome and Human Health
Monday, March 1, 2021, 10:30 am to 5:30 pm (registration required)
NIH Rare Disease Day
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