Stories about: Science

Self-sacrificing cells hold clues to improving treatment of MRSA, sepsis

Image of neutrophils
During infection, white blood cells called neutrophils eject their own DNA strands outward to block bacteria from spreading. IMAGE: ADOBE STOCK

Over the last several years, scientists have made great headway in our understanding of how self-sabotaging immune cells play a role in our ability to fight infection. So far, we know that when white blood cells called neutrophils are triggered by bacterial infection, they self-combust and eject their own DNA strands outward like spider webs. Sacrificing themselves, the exploded neutrophils and their outreaching DNA tentacles form sunburst-shaped neutrophil extracellular traps (NETs).

“NET formation is an innate immune response that our body has when it recognizes the presence of pathogens,” says Ben Croker, PhD, a researcher in the Division of Hematology/Oncology at Boston Children’s Hospital. “Once formed, NETs restrict pathogen movement and proliferation and alert the rest of the immune system to the invader’s presence.”

Now, Croker and a team of researchers at Boston Children’s have identified a critical element of NET formation and how it enables the body to fight off infections like methicillin-resistant Staphylococcus aureus (MRSA). Their findings, recently published in Science Signaling, could someday have clinical implications for tough-to-treat infections and even sepsis.

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Neurons from the brain amplify touch sensation. Could they be targeted to treat neuropathic pain?

neuropathic pain amplification circuit
CREDIT: ALBAN LATREMOLIERE/BOSTON CHILDREN’S HOSPITAL/JOHNS HOPKINS

Neuropathic pain is a hard-to-treat chronic pain condition caused by nervous system damage. For people affected, the lightest touch can be intensely painful. A study in today’s Nature may open up a new angle on treatment — and could help explain why mind-body techniques can sometimes help people manage their pain.

“We know that mental activities of the higher brain — cognition, memory, fear, anxiety — can cause you to feel more or less pain,” notes Clifford Woolf, MB, BCh, PhD, director of the F.M. Kirby Neurobiology Center at Boston Children’s Hospital. “Now we’ve confirmed a physiological pathway that may be responsible for the extent of the pain. We have identified a volume control in the brain for pain — now we need to learn how to switch it off.”

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Typing medulloblastoma: From RNA to proteomics and phospho-proteomics

medulloblastoma proteomics study
Medulloblastoma (CREDIT: ARMED FORCES INSTITUTE OF PATHOLOGY/WIKIMEDIA)

Medulloblastoma is one of the most common pediatric brain tumors, accounting for nearly 10 percent of cases. It occurs in the cerebellum, a complex part of the brain that controls balance, coordination and motor function and regulates verbal expression and emotional modulation. While overall survival rates are high, current therapies can be toxic and cause secondary cancers. Developing alternative therapeutics is a priority for the field.

As early as the 1990s, the lab of Scott Pomeroy, MD, PhD, neurologist-in-chief at Boston Children’s Hospital, discovered molecules in medulloblastoma tumors that could predict response to therapies. In 2010, Pomeroy and colleagues uncovered four distinct molecular subtypes of medulloblastoma.

The World Health Organization updated the brain tumor classification scheme in 2016 to include these molecular and genetic features. In the new scheme, tumor subtypes with a good molecular prognosis receive less radiation and chemotherapy. But the creation of targeted therapeutics has remained a challenge, since some of the genetic pathways implicated in these subtypes are found in non-cancerous cells.

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Blood filtration device could provide personalized care for sepsis

Artistic image of cytokines
Could cell-signaling proteins called cytokines be modulated to tame inflammation? IMAGE: ADOBE STOCK

Cytokines are small proteins produced by the body’s cells that have a big impact on our immune system. Researchers at Boston Children’s Hospital believe that modulating their presence in our bodies could be the key to improving outcomes in life-threatening cases of trauma, hemorrhage and many other conditions including sepsis, which alone impacts nearly one million Americans each year.

The reason? Cells essentially use cytokines to talk to one another. In response to their surroundings, cells release different types of cytokines that encourage inflammatory or anti-inflammatory effects on the body. Infection or trauma causes cells to pump out more cytokines that produce inflammation. Altogether, an escalating chorus of cytokines can sometimes tip a person’s body into overwhelming inflammation that can turn fatal, which is what happens during sepsis.

But what if scientists could remove the problematic cytokines to bring the choir into perfect tune, allowing the immune system to respond with just the right amount of inflammation for healing?

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Tracking the elusive genes that cause strabismus

strabismus genes
(PHOTO: ADOBE STOCK)

Strabismus is a common condition in which the eyes do not align properly, turning inward, outward, upward or downward. Two to four percent of children have some form of it. Some cases can be treated with glasses or eye patching; other cases require eye muscle surgery. But the treatments don’t address the root causes of strabismus, which experts believe is neurologic.

For decades, Elizabeth Engle, MD, in Boston Children’s Hospital’s F.M. Kirby Neurobiology Center, has been studying rare forms of strabismus, such as Duane syndrome, in which strabismus is caused by limited eye movements. Her lab has identified a variety of genes that, when mutated, disrupt the development of cranial nerves that innervate the eye muscles. These genetic findings have led to many insights about motor neurons and how they develop and grow.

More recently, with postdoctoral research fellow Sherin Shabaan, MD, PhD, Engle’s lab has been gathering families with common, non-paralytic strabismus, in which both eyes have a full, normal range of motion yet do not line up properly.

Such “garden variety” forms of strabismus have been much harder to pin down genetically.

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‘See through,’ high-resolution EEG recording array gives a better glimpse of the brain

Transparent microelectrodes allow EEG recording at the single-neuron level, with simultaneous 2-photon optical imaging of calcium activity.
Transparent microelectrodes allow EEG recording at the single-neuron level, with simultaneous 2-photon optical imaging of calcium activity. (CREDIT: Yi Qiang et al. Sci. Adv. 4, eaat0626 (2018).)

Electroencephalography (EEG), which records electrical discharges in the brain, is a well-established technique for measuring brain activity. But current EEG electrode arrays, even placed directly on the brain, cannot distinguish the activity of different types of brain cells, instead averaging signals from a general area. Nor is it possible to easily compare EEG data with brain imaging data.

A collaboration between neuroscientist Michela Fagiolini, PhD at Boston Children’s Hospital and engineer Hui Fang, PhD at Northeastern University has led to a highly miniaturized, see-through EEG device. It promises to be much more useful for understanding the brain’s workings.

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Gene active before birth regulates brain folding, speech motor development

SCN3A, linked to polymicrogyria, regulates speech motor development
ILLUSTRATIONS: RICHARD SMITH/BOSTON CHILDREN’S HOSPITAL

A handful of families from around the world with a rare brain malformation called polymicrogyria have led scientists to discover a new gene that helps us speak and swallow.

The gene, SCN3A, is turned “on” primarily during fetal brain development. When it’s mutated, a language area of the brain known as the perisylvian cortex develops multiple abnormally small folds, appearing bumpy. People with polymicrogyria in this region often have impaired oral motor development, including difficulties with swallowing, tongue movement and articulating words — especially if the polymicrogyria affects both sides of the brain.

The new study, published today in Neuron, ties together human genetics, measurements of electrical currents generated by neurons, studies of ferrets and more to start to connect the dots between SCN3A, the brain malformation and the oral motor impairment.

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Sounding out the protein that enables us to hear

The proposed structure of the TMC1 protein (not to scale), superimposed over rows of hair cells in the mouse inner ear. The yellow portions indicate the amino acid substitutions used to identify the location of the pore that admits ions into the cell. (CREDIT: Bifeng Pan et al., Neuron 2018, https://doi.org/10.1016/j.neuron.2018.07.033)

In 2011, a team led by Jeffrey Holt, PhD, demonstrated that a protein called TMC1 is required for hearing and balance, following the 2002 discovery that mutations in the TMC1 gene cause deafness. Holt’s team proposed that TMC1 proteins form channels that enable electrically charged ions such as calcium and potassium to enter the delicate hair cells of the inner ear. This, in turn, enables the cells to convert sound waves and head movement into electrical signals that talk to the brain.

In a new study published today in Neuron, Holt and colleagues teamed with the lab of David Corey, PhD, at Harvard Medical School. Together, they confirmed TMC1’s essential role in hearing, ending a 40-year quest, and mapped out its working parts.

Working with living hair cells in mice, they made substitutions in 17 amino acids within the TMC1 protein, one at a time, to see which substitutions altered hair cells’ ability to respond to stimuli and allow the flow of ions. Eleven amino acid substitutions altered the influx of ions, and five did so dramatically, reducing ion flow by up to 80 percent. One substitution blocked calcium flow completely, thereby revealing the location of the pore within TMC1 that enables ion influx.

Down the road, the study could have implications for reversing hearing loss, which affects more than 460 million people worldwide.

“To design optimal treatments for hearing loss, we need to know the molecules and their structures where disease-causing malfunctions arise, and our findings are an important step in that direction,” Holt said in this press release from Harvard Medical School.

Read more about Holt’s work.

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Why are males more prone to bladder cancer than females?

A microscopic view of human testis tissue. Researchers have discovered why males are more likely to get bladder cancer than females.
A microscopic view of human testis tissue. Researchers have discovered why males are more likely to get bladder cancer than females. IMAGE: ADOBE STOCK

New research helps explain why men are three to five times more likely to develop bladder cancer than women.

Using mouse models and human patient data, Boston Children’s Hospital researchers in the urology department, Xue Sean Li, PhD, and Satoshi Kaneko, PhD, found that inherent genomic differences contribute to the contrast in bladder cancer rate between males and females.

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A life-saving adjustment in IV nutrition cleared by the FDA

Fourteen years after Charles Rolfe received an experimental IV fish-oil solution, Omegaven has been approved by the FDA. (PHOTOS: WEBB CHAPPELL/ROLFE FAMILY)

In 2004, a surgeon and a hospital pharmacist went against the prevailing dogma. They began revising the IV nutrition formula being given to children unable to take food by mouth. In doing so, they saved many lives. Yet, it wasn’t until last month that their intervention, a new fat emulsion called Omegaven, gained formal approval from the Food and Drug Administration.

Children with intestinal failure due to gastroschisis, necrotizing enterocolitis or other diseases are typically placed on parenteral nutrition, an intravenous method of feeding. Without it, they would die. But prolonged use of IV nutrition — using the traditional formula — had a massive side effect: injury to the liver. The majority of children either died from liver failure or required a liver transplant.

By 2001, surgeon Mark Puder, MD, at Boston Children’s Hospital was tired of watching babies slowly die from liver disease that should be preventable. He suspected something needed to be adjusted in the IV nutrition formula — particularly the fat component, derived from soybean oil and known as Intralipid.

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