Stories about: Science Seen

Science Seen: Disrupted developmental genes cause ‘split brain’

split brain syndrome
The two halves of the brain on the right, from a patient with the DCC mutation, are almost completely disconnected. The mutation — first recognized in worms — prevents axons (nerve fibers) from crossing the midline of the brain by interfering with guidance cues. Image courtesy Ellen Grant, MD, director, Fetal-Neonatal Neuroimaging and Developmental Science Center.

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.

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Science Seen: Brain myelination in tuberous sclerosis complex

tuberous sclerosis brain myelination improved with CTGF deletion

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.)

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Rainbow-hued blood stem cells shed new light on cancer, blood disorders

color-coded blood stem cells
These red blood cells bear color tags made from random combinations of red, green and blue fluorescent proteins. Same-color cells originate from the same blood stem cell (Nature Cell Biology 2016, Henninger 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.

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Science Seen: Worms give a clue to how the nervous system stays organized

nervous system tiling
Courtesy Candice Yip

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.”

Read more in this feature from Harvard Medical School and learn more about Heiman’s research.

 

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Science seen: Stealthy beta cell transplants for diabetes

diabetes encapsulated beta cells Daniel Anderson
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)

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Science seen: A “wheel of death” for bacteria

inflammasome innate immunity

The innate immune system acts like a border patrol for the body, picking up bacteria and other invading pathogens using molecular sensors. One key player is the inflammasome, a multi-protein complex depicted here through cryo-electron microscopy (cryo-EM). Using structural biology tools like cryo-EM and X-ray crystallography, the Wu lab in Boston Children’s Hospital’s Program in Cellular and Molecular Medicine show how protein components come together in inflammasomes to form a “wheel of death” against bacterial infection.

Once they detect an invader, inflammasomes send out signals that trigger infected cells to die using an inflammatory death pathway called pyroptosis. They also call for backup from the adaptive immune system, in the form of inflammation. (Image: Wu laboratory/Liman Zhang)

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Science seen: Mapping touch perception in cerebral palsy

sensory brain mapping in cerebral palsy

Cerebral palsy (CP) is the most common motor disability of childhood. The brain injury causing CP disrupts touch perception, a key component of motor function. In this brain image from a child with CP (click to enlarge), the blue lines show nerve fibers going to the sensory cortex. The colored cubes at the top represent the parts of the sensory cortex receiving touch signals from the thumb (red cube), middle finger (blue) and little finger (green). An injury in the right side of the brain (dark area) has reduced the number of nerve fibers on that side, reducing touch sensation in the left hand and resulting in weakness.

Christos Papadelis, PhD, of Boston Children’s Hospital’s Division of Newborn Medicine hopes to use such sensory mapping information to develop better rehabilitation therapies. P. Ellen Grant, MD, director of the Fetal-Neonatal Neuroimaging and Developmental Science Center, Brian Snyder, MD, of the Cerebral Palsy Program and research assistant Madelyn Rubenstein are part of the team.

 

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Science seen: Oral cancer up close

oral squamous cell carcinoma oral cancer lymphatic system cancer metastasis

Oral squamous cell carcinoma (OSCC), a kind of oral cancer, affects some 30,000 Americans annually. It spreads through the lymphatic system and often has already metastasized by the time it’s diagnosed. The top image here, from a recent study in the American Journal of Pathology, is a healthy mouse tongue; the bottom is the swollen tongue of a mouse with OSCC. The cancerous tongue is overloaded with lymphatic vessels, appearing in blue and white, which help the tumor spread to the regional lymph nodes. The Bielenberg lab in Boston Children’s Hospital’s Vascular Biology Program is studying ways of blocking the progression of this and other cancers by inhibiting their spread through the lymphatic system. (Image: Bielenberg laboratory/Kristin Johnson)

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