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:
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.
Findings may aid design of trials to assess strategies to control HIV without drugs.
A short-term pause in HIV treatment during a carefully monitored clinical trial does not lead to lasting expansion of the HIV reservoir nor cause irreversible damage to the immune system, new findings suggest.
Antiretroviral therapy (ART) benefits the health of people living with HIV, prolongs their lives and prevents transmission of the virus to others. If taken daily as directed, ART can reduce viral load — the amount of HIV in the blood — to levels that are undetectable with standard tests. However, the virus remains dormant in a small number of immune cells, and people living with HIV must take ART daily to keep the virus suppressed. If a person with ART-suppressed HIV stops taking medication, viral load will almost invariably rebound to high levels.
Researchers are working to develop therapeutic strategies to induce sustained ART-free remission — the absence of viral rebound following discontinuation of ART. Clinical trials to assess the efficacy of such experimental therapies may require participants to temporarily stop taking ART, an approach known as analytical treatment interruption, or ATI.
A pill box containing once-daily antiretroviral treatments for HIV infection.
An experimental treatment developed from cattle plasma for Middle East respiratory syndrome (MERS) coronavirus infection shows broad potential, according to a small clinical trial led by National Institutes of Health scientists and their colleagues. The treatment, SAB-301, was safe and well tolerated by healthy volunteers, with only minor reactions documented.
The first confirmed case of MERS was reported in Saudi Arabia in 2012. Since then, the MERS coronavirus has spread to 27 countries and sickened more than 2,000 people, of whom about 35 percent have died, according to the World Health Organization. There are no licensed treatments for MERS.
SAB-301 was developed by SAB Biotherapeutics of Sioux Falls, South Dakota, and has been successfully tested in mice. The treatment comes from so-called “transchromosomic cattle.” These cattle have genes that have been slightly altered to enable them to produce fully human antibodies instead of cow antibodies against killed microbes with which they have been vaccinated — in this case the MERS virus. The clinical trial, conducted by NIH’s National Institute of Allergy and Infectious Diseases, took place at the NIH Clinical Center.
The round, spiked objects at center are MERS coronavirus particles.
Stem cell-derived retinal cells need primary cilia to support survival of light-sensing photoreceptors.
Scientists at the National Eye Institute (NEI), part of the National Institutes of Health, report that tiny tube-like protrusions called primary cilia on cells of the retinal pigment epithelium (RPE) — a layer of cells in the back of the eye — are essential for the survival of the retina’s light-sensing photoreceptors. The discovery has advanced efforts to make stem cell-derived RPE for transplantation into patients with geographic atrophy, otherwise known as dry age-related macular degeneration (AMD), a leading cause of blindness in the U.S. The study appears in the January 2 Cell Reports.
“We now have a better idea about how to generate and replace RPE cells, which appear to be among the first type of cells to stop working properly in AMD,” said the study’s lead investigator, Kapil Bharti, Ph.D., Stadtman Investigator at the NEI. Bharti is leading the development of patient stem cell-derived RPE for an AMD clinical trial set to launch in 2018.
In a healthy eye, RPE cells nourish and support photoreceptors, the cells that convert light into electrical signals that travel to the brain via the optic nerve. RPE cells form a layer just behind the photoreceptors. In geographic atrophy, RPE cells die, which causes photoreceptors to degenerate, leading to vision loss.
Mature iPSC-derived RPE cells under super resolution
Since 2016, when Zika was declared by WHO as a public health emergency of international concern, the virus has become established in more than 80 countries, infected millions of people, and left many babies with birth defects (collectively called congenital Zika syndrome). Although scientists have made progress in their understanding of the virus and its mosquito carrier, and are working toward treatments and a preventive vaccine, it would be premature to think that the Zika pandemic is now under control and will not reemerge, perhaps more aggressively, say leaders from the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health. The Journal of Infectious Diseases published online December 16 a special supplement of articles examining current scientific knowledge about the Zika virus and the key research questions that remain. The supplement was sponsored and edited by NIAID and features several articles written by NIAID scientists.
Zika virus particles (red) shown in African green monkey kidney cells
Plant molecule could be used to block postoperative incisional pain.
A promising approach to post-operative incision-site pain control uses a naturally occurring plant molecule called resiniferatoxin (RTX). RTX is found in Euphorbia resinifera, a cactus-like plant native to Morocco, which is 500 times more potent than the chemical that produces heat in hot peppers, and may help limit the use of opioid medication while in the hospital and during home recovery.
In a paper published online in Anesthesiology, the peer-reviewed medical journal of the American Society of Anesthesiologists, researchers found that RTX could be used to block postoperative incisional pain in an animal model. Many medical providers turn to opioids, such as morphine or fentanyl, for moderate to severe post-operative pain relief, but these often come with side effects that can interfere with recovery, including respiratory depression, inhibition of gut motility and constipation, nausea and vomiting. Prolonged use of opioids can produce tolerance and introduces the risk of misuse. RTX is not an opioid and does not act in the brain but rather on the nerve endings in the skin. Scientists found that it can be used to block pain from the surgical incision selectively for approximately 10 days.
