Interestingly, the same portal, known as the Frizzled receptor, also receives signals that maintain the intestine’s stem cells. When toxin B docks, it blocks these signals, carried by a molecule known as Wnt. But exactly how it all works remained a puzzle — until new research published today in Science.
Liang Tao, PhD in Dong’s lab, working with the labs of Rongsheng Jin, PhD, at UC-Irvine, and Xi He, PhD, at Boston Children’s, captured the crystal structure of a fragment of toxin B (in orange above) as it joined to the Frizzled receptor (in green). The structure revealed lipid molecules within the Frizzled receptor (in yellow and red) that play a central role. Normally, when Wnt binds to Frizzled, it nudges these lipids aside. But the team showed that when the toxin fragment binds to Frizzled, it locks these lipids in place, preventing Wnt from engaging with the cell.
Just as stem cells rely on Wnt signaling for growth and regeneration, so do many cancers. Now that its mechanism is known, Dong thinks this toxin B fragment, which by itself isn’t toxic, could be a useful anti-cancer therapeutic. They’re currently developing a new generation of Wnt signaling modulators and testing them in animal models of cancer. (For further information, contact Rajinder.Khunkun@childrens.harvard.edu of Boston Children’s Technology & Innovation Development Office.)
Astronomers developed a “guide star” adaptive optics technique to obtain the most crystal-clear and precise telescopic images of distant galaxies, stars and planets. Now a team of scientists, led by Nobel laureate Eric Betzig, PhD, are borrowing the very same trick. They’ve combined it with lattice light-sheet to create a new microscope that’s able to capture real-time, incredibly detailed and accurate images, along with three-dimensional videos of biology on the cellular and sub-cellular level.
The work — a collaboration between researchers at Howard Hughes Medical Institute, Boston Children’s Hospital and Harvard Medical School — is detailed in a new paper just published in Science.
“Every time we’ve done an experiment with this microscope, we’ve observed something novel — and generated new ideas and hypotheses to test,” Kirchhausen said in a news story by HMS. “It can be used to study almost any problem in a biological system or organism I can think of.” …
Babies can hear and respond to sounds, including language, before birth. In fact, research shows that babies learn to recognize words in the womb. Now, an advanced MRI technique called diffusion tensor imaging is providing a fine-tuned view of when different brain areas mature, including the areas that process sound. And the findings suggest that babies born prematurely may have disruptions in auditory brain development and in speech.
Investigators at Boston Children’s Hospital, Brigham and Women’s Hospital, Washington University School of Medicine in St. Louis and University College London analyzed advanced MRI brain images from 90 preterm infants and 15 infants born at full term (40 weeks). Fifty-six of the preterm infants were imaged at multiple time points. As shown above, the team focused on a particular fold in the brain called Heschl’s gyrus (HG). This area contains the primary auditory cortex, the first part of the auditory cortex to receive sound signals, and the non-primary auditory cortex, which plays a higher-level role in processing those stimuli.
As seen in these sample images, the primary cortex has largely matured at 28 weeks’ postmenstrual age (PMA), whereas the non-primary auditory cortex has had a surge in development between 28 and 40 weeks’ PMA. Both regions appeared underdeveloped in the premature infants as compared with the infants born at term.
The study further found that disturbed maturation of the non-primary cortex was associated with poorer expressive language ability at age 2. The team suggests that this area may be especially vulnerable to disruption in a premature birth because it is undergoing such rapid change.
The study was published in eNeuro, an open-access journal from the Society for Neuroscience. Jeffrey Neil, MD, PhD, of Boston Children’s Department of Neurology, was senior author on the paper. First author Brian Monson, PhD, is now at the University of Illinois at Urbana-Champaign. Read more in the university’s press release.
Rotavirus, a major cause of early childhood diarrhea, could have a lot to tell drug developers about how to deliver their products into cells.
Rotavirus doesn’t have an outer membrane, so it’s had to evolve a special system to infect cells. “Viruses with a membrane, like flu or HIV, can simply fuse that membrane with the membrane of the target cell and dump their contents inside the cell,” says Stephen Harrison, PhD, chief of the Laboratory of Molecular Medicine at Boston Children’s Hospital.
Rotavirus does something different, Harrison’s lab has found. First, each virion attaches itself to the cell membrane and wraps itself inside it. Next, its outer proteins, VP4 (the red spikes above) and VP7 (in yellow), disrupt that membrane — and are stripped off in a matter of seconds.
“If you will, they’re the booster the rocket has to shed so the payload can continue,” says Harrison. …
Staphylococcus aureus causes 11,000 deaths annually in the U.S. alone and is frequently antibiotic-resistant. It’s a leading cause of pneumonia, bloodstream infections, bone/joint infections and surgical site infections and the #1 cause of skin and soft tissue infections. Efforts to develop an S. aureus vaccine have so far failed: the vaccines don’t seem to be capturing the right ingredients to make people immune.
Kristin Moffitt, MD, in Boston Children’s Hospital’s Division of Infectious Diseases, took a step back and asked: “What proteins does S. aureus need to make to establish infection?” The answer, she reasoned, could point to new antigens to include in a vaccine.
The above image shows an early result from Moffitt’s investigation. It’s a “heat map” of the messenger RNA signature — a snapshot of the proteins S. aureus is potentially up-regulating during infection. …
Tim Yu, MD, PhD, a neurologist and genomics researcher at Boston Children’s Hospital, was studying autism genes when he saw something on a list that rang a bell. It was a mutation that completely knocked out the so-called Deleted in Colorectal Carcinoma gene (DCC), originally identified in cancer patients. The mutation wasn’t in a patient with autism, but in a control group of patients with brain malformations he’d been studying in the lab of Chris Walsh, MD, PhD.
Yu’s mind went back more than 20 years. As a graduate student at University of California, San Francisco, he’d conducted research in roundworms, studying genetic mutations that made the worms, which normally move in smooth S-shaped undulations, move awkwardly and erratically. …
Tuberous sclerosis complex (TSC) strikes about 1 in 6,000 people and is marked by numerous benign tumors in the brain, kidneys, heart, lungs and other tissues. Children with TSC often have epilepsy, intellectual disability and/or autism, showing disorganized white matter in their brains. Work in the lab of Mustafa Sahin, MD, PhD, has shown that the TSC1 mutation disrupts the brain’s ability to adequately wrap its nerve fibers in myelin, the insulating coating that enhances nerves’ ability to conduct signals. A new study from the lab shows why: neurons lacking functional TSC1 secrete increased amounts of connective tissue growth factor (CTGF). This impairs the development of oligodendrocytes, the cells that do the myelinating. Here, electron microscopy in a TSC mouse model shows a decreased number of nerve fibers wrapped in myelin (dark ovals) on the left. On the right, genetic deletion of CTGF increases myelination. Sahin plans to delve further to develop potential pharmaceutical approaches to restore myelination in TSC. Read more in the Journal of Experimental Medicine. (Image: Ebru Ercan et al.)
A new color-coding tool is enabling scientists to better track live blood stem cells over time, a key part of understanding how blood disorders and cancers like leukemia arise, report researchers in Boston Children’s Hospital’s Stem Cell Research Program.
In Nature Cell Biology today, they describe the use of their tool in zebrafish to track blood stem cells the fish are born with, the clones (copies) these cells make of themselves and the types of specialized blood cells they give rise to (red cells, white cells and platelets). Leonard Zon, MD, director of the Stem Cell Research Program and a senior author on the paper, believes the tool has many implications for hematology and cancer medicine since zebrafish are surprisingly similar to humans genetically. …
To the eye, nervous systems look like a tangled mess of neurons and their tree-like branches known as dendrites, but it’s really organized chaos. How the system finds order has intrigued but eluded scientists. In the worm C. elegans, Max Heiman, PhD and graduate student Candice Yip found an elegant system to help explain how neurons each maintain their own space.
Normally, worms have just one neuron of a certain type on either side of their bodies. Yip did a “forward genetic screen” — mutating genes at random to find factors important for neuron wiring. One mutation caused the worm to grow not one set of neurons but five. By engineering the neurons to make a color-changing signal — as shown above — Yip showed that these extra neurons didn’t overlap with each other, but instead carved out discrete territories — a phenomenon known as tiling. How?
Acting on a hunch, Yip and Heiman, of Harvard Medical School and Boston Children’s Hospital’s Division of Genetics and Genomics, showed that C. elegans, faced with an increase in neurons, pressed a molecule called netrin into service to enforce boundaries between them. Netrin is better known for helping nerve fibers navigate to their destinations. When Yip took netrin out of action, the dendrites from the five neurons crossed the invisible borders and grew entangled.
The findings, published today in Cell Reports, could provide insight into neuropsychiatric diseases, believes Heiman, also part of Boston Children’s F.M. Kirby Neurobiology Center. “It’s fundamental to neuropsychiatric disease to make sure brain wiring goes right,” he says. “This is also story about how new features evolve, and how you can form something as complicated as a nervous system. There are pathways that bring everything into order.”
Type 1 diabetes afflicts more than 300 million people worldwide. Researchers have long sought a way to replace the insulin-producing beta cells lost in the disease, but transplanted cells are susceptible to immune attack. In this image, beta cells generated from human embryonic stem cells are encapsulated in microspheres made from a material called alginate, which help cloak the cells from the immune system. However, the reddish, blue and green markers on the spheres’ surfaces indicate that immune cells have discovered spheres and their cargo, and begun to block them off from the rest of the body.
In simultaneous papers in Nature Medicine and Nature Biotechnology, Daniel Anderson, PhD — a professor of applied biology at MIT and a researcher in Boston Children’s Hospital’s Department of Anesthesia, Perioperative and Pain Medicine — and his collaborators reported on their search for effective cloaking materials They also announced that microsphere-encapsulated beta cells can reverse diabetes in a mouse model. With further work on the microspheres’ chemistry and geometry, the team hopes to improve their cloaking abilities and provide longer lasting protection for beta cells. (Image: Andrew Bader, Omid Veiseh, Arturo Vegas, Anderson/Langer Laboratory, Koch Institute at MIT)