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:
Mouse nicotinamide riboside study shows potential for human research
The supplement nicotinamide riboside (NR) – a form of vitamin B3 – prevented neurological damage and improved cognitive and physical function in a new mouse model of Alzheimer’s disease. The results of the study, conducted by researchers at the National Institute on Aging (NIA) part of the National Institutes of Health, suggest a potential new target for treating Alzheimer’s disease. The findings appear in the Feb. 5, 2018, issue of Proceedings of the National Academy of Sciences.
NR acts on the brain by normalizing levels of nicotinamide adenine dinucleotide (NAD+), a metabolite vital to cellular energy, stem cell self-renewal, resistance to neuronal stress and DNA repair. In Alzheimer’s disease, the brain’s usual DNA repair activity is impaired, leading to mitochondrial dysfunction, lower neuron production, and increased neuronal dysfunction and inflammation.
The international team of scientists was led by Vilhelm A. Bohr, M.D., Ph.D., senior investigator and chief of the Laboratory of Molecular Gerontology of the NIA’s Intramural Research Program, with Dr. Yujun Hou, a postdoctoral investigator in the laboratory.
In a mouse model of Alzheimer’s disease, amyloid beta clusters (red) build up among neurons (green) in a memory-related area of the brain. With support from the National Center for Advancing Translational Sciences, scientists have found that a compound originally developed as a cancer therapy potentially could be used to treat Alzheimer’s disease.
High exposure to radiofrequency radiation (RFR) in rodents resulted in tumors in tissues surrounding nerves in the hearts of male rats, but not female rats or any mice, according to draft studies from the National Toxicology Program (NTP). The exposure levels used in the studies were equal to and higher than the highest level permitted for local tissue exposure in cell phone emissions today. Cell phones typically emit lower levels of RFR than the maximum level allowed. NTP’s draft conclusions were released today as two technical reports, one for rat studies and one for mouse studies. NTP will hold an external expert review of its complete findings from these rodent studies March 26-28.
The incidence of tumors, called malignant schwannomas, that were observed in the heart increased in male rats as they were exposed to increasing levels of RFR beyond the allowable cell phone emissions. Researchers also noted increases in an unusual pattern of cardiomyopathy, or damage to heart tissue, in exposed male and female rats. Overall, there was little indication of health problems in mice related to RFR.
The reports also point out statistically significant increases in the number of rats and mice with tumors found in other organs at one or more of the exposure levels studied, including the brain, prostate gland, pituitary gland, adrenal gland, liver, and pancreas. However, the researchers determined that these were equivocal findings, meaning it was unclear if any of these tumor increases were related to RFR.
“The levels and duration of exposure to RFR were much greater than what people experience with even the highest level of cell phone use, and exposed the rodents’ whole bodies. So, these findings should not be directly extrapolated to human cell phone usage,” said John Bucher, Ph.D., NTP senior scientist. “We note, however, that the tumors we saw in these studies are similar to tumors previously reported in some studies of frequent cell phone users.”
Scientists looking for jobs after completing their training may soon have a new tool that helps them evaluate various career paths. The new tool uses a method that was developed by scientists at the National Institute of Environmental Health Sciences (NIEHS), part of the National Institutes of Health. The method differs from others in that it separates employment trends in biomedical science by sector, type, and job specifics. The creators hope this novel approach will be useful throughout NIH, as well as for academic and research institutions around the world.
Led by Tammy Collins, Ph.D., director of the NIEHS Office of Fellows’ Career Development, team members collected detailed career outcomes for more than 900 NIEHS postdoctoral fellows over the past 15 years. Postdoctoral fellows, or postdocs, are scientists who have received their doctoral degrees and are participating in a program that offers additional training.
Lead author and NIEHS computer scientist Hong Xu analyzed the data using the R Project for Statistical Computing, a free online program that displays data using graphs and charts. Shyamal Peddada, Ph.D., former NIEHS head of the Biostatistics and Computational Biology Branch, served as key advisor. The study appeared online in the journal Nature Biotechnology, and is the first standardized method for categorizing career outcomes of NIEHS postdocs.
The study categorized career outcomes for NIEHS postdocs by sector, type, and job specifics. The authors envision that this approach will help young scientists make career decisions based on data and not anecdotal evidence.
NIH clinical trial is testing antibody against the protein in people with HIV.
For the first time, scientists have shown a relationship between the proportion of key immune cells that display high levels of a gut-homing protein called alpha-4 beta-7 at the time of HIV infection and health outcomes. Previous research illustrated this relationship in monkeys infected with a simian form of HIV.
The new study found that women who had more CD4+ T cells displaying high levels of alpha-4 beta-7 on their surface were more likely to become infected with HIV, and the virus damaged their immune systems more rapidly, than women with fewer such cells. The National Institutes of Health co-funded the study with the South African Medical Research Council as part of the U.S.–South Africa Program for Collaborative Biomedical Research. In addition, NIH scientists collaborated on the study. The report appears online today in the journal Science Translational Medicine.
“Our findings suggest that having a high frequency of alpha-4 beta-7-expressing CD4+ T cells, which HIV preferentially infects, leads to more HIV-infected CD4+ T cells moving to the gut, which in turn leads to extensive damage to gut-based immune cells,” said Anthony S. Fauci, M.D. Dr. Fauci co-authored the paper as chief of the Laboratory of Immunoregulation at the National Institute of Allergy and Infectious Diseases (NIAID), part of NIH. He also is director of NIAID.
Scanning electron micrograph of a human T lymphocyte (also called a T cell) from the immune system of a healthy donor.
People with higher levels of antibodies against the stem portion of the influenza virus hemagglutinin (HA) protein have less viral shedding when they get the flu, but do not have fewer or less severe signs of illness, according to a new study published in mBio. HA sits on the surface of the influenza virus to help bind it to cells and features a head and stem region. Scientists only recently discovered that humans naturally generate anti-HA stem antibodies in response to flu infection, and this is the first study of its kind to evaluate pre-existing levels of these specific antibodies as a predictor of protection against influenza. The findings could have implications for flu vaccine development, according to the authors. Scientists at the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, conducted the research.
The study team has explored immune responses to two influenza surface proteins: HA—the main target of traditional seasonal flu vaccines—and neuraminidase (NA). The head region of HA is constantly changing, which is why influenza vaccine strains must be updated each year. The HA stem region, however, is less susceptible to change, making it a potential target for novel vaccines aimed at broader, more durable protection.
In the new analysis, investigators sought to understand the role of pre-existing anti-HA stem antibodies in protection against influenza using data from a healthy volunteer influenza challenge trial that took place in 2013 at the NIH Clinical Center in Bethesda, Maryland. Led by NIAID’s Matthew J. Memoli, M.D., the trial enrolled 65 healthy volunteers aged 18 to 50 years. Participants stayed in a specially designed isolation and infection control unit throughout the study. Investigators measured participants’ baseline levels of anti-HA stem antibodies, infected them with a 2009 H1N1 influenza virus, and then measured levels of anti-HA stem antibodies again.
3D print of hemagglutinin (HA), one of the proteins found on the surface of influenza virus that enables the virus to infect human cells. In this model, blue and purple denote areas where mutations can change the ability of the virus to attach to host cells and cause infection.
Beneficial bacteria on the skin of lab mice work with the animals’ immune systems to defend against disease-causing microbes and accelerate wound healing, according to new research from scientists at the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health. Researchers say untangling similar mechanisms in humans may improve approaches to managing skin wounds and treating other damaged tissues. The study was published online today in Cell.
Like humans and other mammals, mice are inhabited by large, diverse microbial populations collectively called the microbiome. While the microbiome is believed to have many beneficial functions across several organ systems, little is known about how the immune system responds to these harmless bacteria.
To investigate, NIAID scientists led by Yasmine Belkaid, Ph.D., chief of the Mucosal Immunology Section of NIAID’s Laboratory of Parasitic Diseases, observed the reaction of mouse immune cells to Staphylococcus epidermidis, a bacterium regularly found on human skin that does not normally cause disease. To their surprise, immune cells recognized S. epidermidis using evolutionarily ancient molecules called non-classical MHC molecules, which led to the production of unusual T cells with genes associated with tissue healing and antimicrobial defense. In contrast, immune cells recognize disease-causing bacteria with classical MHC molecules, which lead to the production of T cells that stoke inflammation.
Immunofluorescent image of immune cells surrounding a skin wound, enriched in the beneficial bacteria S. epidermidis.
NTP coordinates toxicology research and testing across nine different federal agencies.
The National Toxicology Program (NTP) has named Brian Berridge, D.V.M., Ph.D., as its new Associate Director. Berridge, formerly of GlaxoSmithKline, will oversee day-to-day operations as NTP coordinates toxicology research and testing across nine different federal agencies, including the National Institutes of Health, the U.S. Food and Drug Administration, and the Centers for Disease Control and Prevention. Berridge is replacing John Bucher, Ph.D., who has served as Associate Director since 2007 and plans to continue with NTP as a senior scientist.
Berridge will take over guidance of NTP products like the congressionally mandated Report on Carcinogens, which currently lists 248 cancer-causing agents, and scientific literature reviews on topics like fluoride that are nominated to NTP by other agencies or the public. He will also help oversee toxicological studies on topics such as chemical spills and cell phones. Since 1978, NTP has evaluated more than 2,800 chemicals and other agentsfor a variety of health-related effects, like contributing to cancer or being toxic to reproductive, immune, or nervous systems. NTP is headquartered at the National Institute of Environmental Health Sciences (NIEHS), part of NIH.
“We are thrilled that Dr. Berridge is bringing his expertise to environmental health, including experience with both traditional and novel toxicological methods,” said Linda Birnbaum, Ph.D., who has been the director of NTP since 2009, while also directing NIEHS. “We are also deeply appreciative of Dr. Bucher’s exemplary leadership for the past decade.”
Brian Berridge, D.V.M, Ph.D. is the new associate director of the National Toxicology Program.
No longer the future of medicine, gene therapy is part of present-day clinical treatment.
After three decades of hopes tempered by setbacks, gene therapy—the process of treating a disease by modifying a person’s DNA—is no longer the future of medicine, but is part of the present-day clinical treatment toolkit. The Jan. 12 issue of the journal Science provides an in-depth and timely review of the key developments that have led to several successful gene therapy treatments for patients with serious medical conditions.
Co-authored by Cynthia E. Dunbar, M.D., senior investigator at the Hematology Branch of the National Heart, Lung and Blood Institute (NHLBI), part of the National Institutes of Health, the article also discusses emerging genome editing technologies. According to Dunbar and her colleagues, these methods, including the CRISPR/Cas9 approach, would provide ways to correct or alter an individual's genome with precision, which should translate into broader and more effective gene therapy approaches.
Gene therapy is designed to introduce genetic material into cells to compensate for or correct abnormal genes. If a mutated gene causes damage to or spurs the disappearance of a necessary protein, for example, gene therapy may be able to introduce a normal copy of the gene to restore the function of that protein.
Colorized scanning electron micrograph of a T lymphocyte. The engineering of lymphocytes, white blood cells, can be used in the targeted killing of cancer cells.
Women with moderate to severe iodine deficiency may take longer to achieve a pregnancy, compared to women with normal iodine levels, according to a study by researchers at the National Institutes of Health. The study is the first to investigate the potential effects of mild to moderate iodine deficiency — common among women in the United States and the United Kingdom — on the ability to become pregnant. It appears in the latest edition of Human Reproduction.
Iodine is a mineral used by the body to regulate metabolism. It also helps regulate bone growth and brain development in children. It is found in seafood, iodized salt, dairy products, and some fruits and vegetables. Severe iodine deficiency has long been known to cause intellectual and developmental delays in infants.
“Our findings suggest that women who are thinking of becoming pregnant may need more iodine,” said James L. Mills, M.D., who conducted the study along with colleagues at NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development and the New York State Department of Health in Albany. “Iodine requirements increase during pregnancy, and the fetus depends on this mineral to make thyroid hormone and to ensure normal brain development.”
Finding promises to improve drug design for common forms of cancer.
The first three-dimensional structure of DHHC proteins — enzymes involved in many cellular processes, including cancer — explains how they function and may offer a blueprint for designing therapeutic drugs. Researchers have proposed blocking DHHC activity to boost the effectiveness of first-line treatments against common forms of lung and breast cancer. However, there are currently no licensed drugs that target specific DHHC enzymes. The study, led by researchers at the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), appears in the latest issue of Science. NICHD is part of the National Institutes of Health.
DHHC enzymes, also called palmitoyltransferases, modify other proteins by attaching to them a chain of lipids, or fatty acids, of varying lengths. This modification, called palmitoylation, can change many properties of a target protein, such as its structure, function and location within a cell. Researchers estimate that nearly 1,000 human proteins undergo palmitoylation, including epidermal growth factor receptors (EGFRs). A well-known EGFR is HER2, which is overactivated in aggressive forms of breast cancer. EGFRs can also be overactivated in colon cancer, and non-small cell lung cancer, the most common type of lung cancer.
The current study details the structures of a human DHHC enzyme, DHHC20, and the zebrafish version of another DHHC enzyme, DHHC15. Importantly, DHHC20 is the enzyme that palmitoylates EGFR. Previous studies have shown that blocking DHHC20 makes cancer cells more vulnerable to existing FDA-approved treatments that target EGFR. Therefore, understanding the structure of DHHC20 may be important for treating EGFR-driven cancers.
“Mutations in DHHC enzymes are associated with various cancers and neurological disorders,” according to Anirban Banerjee, Ph.D., the study’s lead author and head of NICHD’s Unit on Structural and Chemical Biology of Membrane Proteins. “Our study offers a starting point for developing DHHC20 inhibitors that may aid in treatment of common cancers and advance the field of protein palmitoylation.”
Molecular view of DHHC palmitoyltransferases. Human DHHC20 (yellow) is embedded in the Golgi membrane (green), a compartment located inside cells. DHHC20 attaches a fatty acid chain (white) to a target protein (blue, foreground), which anchors the protein to the Golgi membrane.
