Master clock in mouse brain with the nuclei of the clock cells shown in blue and the VIP molecule shown in green. Credit: Cristina Mazuski in the lab of Erik Herzog, Washington University in St. Louis.
Our biological clocks play a large part in influencing our sleep patterns, hormone levels, body temperature and appetite. A small molecule called VIP, shown in green, enables time-keeping neurons in the brain’s central clock to coordinate daily rhythms. New research shows that, at least in mice, higher doses of the molecule can cause neurons to get out of synch. By desynchronizing mouse neurons with an extra burst of VIP, Erik Herzog of Washington University in St. Louis found that the cells could better adapt to abrupt changes in light (day)-dark (night) cycles. The finding could one day lead to a method to reduce jet lag recovery times and help shift workers better adjust to schedule changes.
Inflammation is part of the body’s natural response to trauma, but when it becomes widespread, it can lead to sepsis. Credit: U.S. Navy.
Inflammation is part of the body’s natural response to trauma, playing a vital role in wound healing and prevention of infection. However, when inflammation becomes widespread, or systemic, it can lead to sepsis, a condition that can damage organs and cause death. Scientists led by Ping Wang of the Feinstein Institute for Medical Research have found a way to potentially target harmful systemic inflammation. They identified a protein–cold-inducible RNA-binding protein (CIRP)–that triggers inflammatory responses during hemorrhagic shock and sepsis. Wang then hypothesized that blocking CIRP activity might mitigate the body’s overall inflammatory response and improve patient survival. In a preclinical study using mice, an antibody against CIRP decreased mortality after hemorrhage and sepsis. The molecule could lead to the development of an anti-CIRP drug.
This work also was funded by the NIH Office of the Director and NIH’s National Heart, Lung, and Blood Institute.
The interactions of TMEM24 protein (green) and insulin (red) in pancreatic beta cells are shown in yellow. Credit: Balch Lab, the Scripps Research Institute. View larger image
The identities of the proteins that drive insulin production and release from pancreatic beta cells have largely been a mystery. In new work from the lab of William Balch of the Scripps Research Institute, researchers isolated and then identified all the insulin-bound proteins from mouse beta cells. The results provided a roadmap of the protein interactions that lead to insulin production, storage and secretion. The researchers used the roadmap to identify a protein called TMEM24, which was abundant in beta cells and binds readily to insulin. Balch and his team uncovered that TMEM24, whose involvement in insulin secretion was previously unknown, effectively regulates slower insulin release and could have a key role in maintaining control of glucose levels in the blood. The scientists hope that this roadmap of insulin-interacting proteins will lead to the development of new, targeted approaches to treating type 2 diabetes and a similar insulin-related condition called metabolic syndrome.
Messenger proteins help the cell make large projections (left). When these proteins aren’t activated, the cell doesn’t move (right). Credit: Devreotes Lab, Johns Hopkins University School of Medicine. View larger image
A new study from Peter Devreotes, Pablo Iglesias and other scientists at Johns Hopkins University sheds light on the way in which cells get around the body to promote embryo development, wound healing and even cancer metastasis. Here’s how they describe cell movement and their findings:
Think of the cell as a rowboat. Sensor proteins on the outside pass on directional signals to messenger proteins that serve as the cell’s coxswain. The coxswain then commands other members of the molecular crew to stay in sync, propelling the cell forward. If there are no sensor signals, the coxswain can still coordinate the cell’s movement, just not in any specific direction—it’s like a boat without a rudder.
Scientists previously thought that the messenger proteins needed the sensor ones to produce both directional and random movements. Because defects in the messenger proteins have been linked to many types of cancer, the new work suggests these molecules could serve as a drug target for immobilizing tumor cells.
Learn more:
New insight into the genes that affect drug responses may help doctors prescribe the medications and doses best suited for each individual. Credit: Jane Ades, NIH’s National Human Genome Research Institute.
Scientists know that variations in certain genes can affect the way a person responds to medications. New research by Wolfgang Sadee at Ohio State University shows that drug responses also depend on previously overlooked parts of DNA—sections that regulate genes, but are not considered genes themselves. This study focused on an important enzyme abbreviated CYP2D6 that processes about one-fourth of all prescription drugs. Differences in the enzyme’s performance, which range from zilch to ultra-rapid, can dramatically alter the effectiveness and safety of certain medications. Researchers discovered two new genetic variants that impact CYP2D6 performance. One of these, located in a non-gene, regulatory region of DNA, doubles or even quadruples enzyme activity. Coupling these findings with genetic tests could help doctors better identify each patient’s CYP2D6 activity level, enabling more precise prescriptions. The findings also open up a whole new area of investigation into genetic factors that impact drug response.
This work also was funded by NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development.
Learn more:
Ohio State University News Release (no longer available)
Treating yeast cells with the NAB compound reverses the toxic effects of elevated levels of alpha synuclein protein. Credit: Daniel Tardiff, Whitehead Institute. View larger image
These eye-catching images and the NIGMS-funded research that yielded them were recently featured by NIH Director Francis Collins on his blog. Scientists led by a team at the Whitehead Institute for Biomedical Research engineered yeast to produce too much of a protein, alpha synuclein. In Parkinson’s disease, elevated levels or mutated forms of this protein wreak havoc on the cell. Using the model system, the researchers tested tens of thousands of compounds to identify any that reversed the toxic effects. One did. The compound, abbreviated NAB, worked similarly in an animal model and in rat neurons grown in a lab dish. Collins described the approach as “an innovative strategy for drug hunting that will likely be extended to other conditions.”
Emily Scott Field: Biochemistry Works at: University of Kansas in Lawrence Favorite hobby: Scuba diving Likes watching: “Law & Order” Likes reading: True-life survival stories
Credit: Chuck France, University of Kansas
With an air tank strapped to her back, college student Emily Scott dove to the bottom of the Gulf of Mexico to examine life in an oxygen-starved area called the Dead Zone. The bottom waters had once teemed with red snapper, croaker and shrimp, but to Scott, the region appeared virtually devoid of life. Then, from out of the mud, appeared the long, undulating arms of a brittle star.
As Scott learned, that particular species of brittle star survived in the Dead Zone because it has something many other marine creatures don’t: an oxygen-carrying protein called hemoglobin. This same protein makes our blood red. Key to hemoglobin’s special oxygen-related properties is a small molecular disk called a heme (pronounced HEEM).
Once she saw what it meant to brittle stars, Scott was hooked on heme and proteins that contain it.
Scott’s Findings
Now an associate professor, Scott studies a family of heme proteins called cytochromes P450 (CYP450s). These proteins are enzymes that facilitate many important reactions: They break down cholesterol, help process vitamins and play an important role in flushing foreign chemicals out of our systems.
To better understand CYP450s, Scott uses a combination of two techniques–X-ray crystallography and nuclear magnetic resonance spectroscopy—for capturing the enzymes’ structural and reactive properties.
She hopes to apply her work to design drugs that block certain CYP450 reactions linked with cancer. One target reaction, carried out by CYP2A13, converts a substance in tobacco into two cancer-causing molecules. Another target reaction is carried out by CYP17A1, an enzyme that helps the body produce steroid sex hormones but that, later in life, can fuel the uncontrolled growth of prostate or breast cancer cells.
“I’m fascinated by these proteins and figuring out how they work,” Scott says. “It’s like trying to put together a puzzle—a very addictive puzzle.” Her drive to uncover the unknown and her willingness to apply new techniques have inspired the students in her lab to do the same.
Content adapted from“Hooked on Heme,” an article in the September 2013 issue of Findings magazine.
Credit: Yaron Fuchs and Samara Brown in the lab of Hermann Steller, Rockefeller University.
Whether injured by a scrape, minor burn or knife wound, skin goes through the same steps to heal itself. Regrowing hair over new skin is one of the final steps. All the hair you can see on your body is non-living, made up of “dead” cells and protein. It sprouts from living cells in the skin called hair follicle stem cells, shown here in red and orange. For more pictures of hair follicle stem cells—and many other stunning scientific images and videos—go to the NIGMS Image and Video Gallery.
Influenza virus proteins in the act of self-replication. Credit: Wilson, Carragher and Potter labs, Scripps Research Institute.
Flu viruses evolve rapidly, often staying one step ahead of efforts to vaccinate against infections or treat them with antiviral drugs. Work led by Jesse Bloom of the Fred Hutchinson Cancer Research Center has uncovered a surprising new flu mutation that allows influenza to infect cells in a novel way. Normally, a protein called hemagglutinin lets flu viruses attach to cells, and a protein called neuraminidase lets newly formed viruses escape from infected cells. Bloom’s lab has characterized a mutant flu virus where neuraminidase can enable the virus to attach to host cells even when hemagglutinin’s binding is blocked. Although the researchers generated the neuraminidase mutant studied in these experiments in their lab, the same mutation occurs naturally in strains from several recent flu outbreaks. There’s a possibility that flu viruses with such mutations may be able to escape antibodies that block the binding of hemagglutinin.
This work also was funded by NIH’s National Institute of Allergy and Infectious Diseases.
Cancer tumors are like snowflakes—no two ever share the same genetic mutations. Their unique characteristics make them difficult to categorize and treat. A new approach proposed by Trey Ideker and his team at the University of California, San Diego, might offer a solution. Their approach, called network-based stratification (NBS), identifies cancer subtypes by how different mutations in different cancer patients affect the same biological networks, such as genetic pathways. As proof of principle, they applied the method to ovarian, uterine and lung cancer data to obtain biological and clinical information about mutation profiles. Such cancer subtyping shows promise in helping to develop more effective, personalized treatments.
Learn more:
University of California, San Diego News Release Ideker Lab
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