Author: Kat J. McAlpine

Mitigating blood vessel damage from heart attack, stroke

Mouse hearts showing the impact of a therapeutic protein fusion on blood vessel health
Imaging of mouse hearts reveals widespread tissue damage (light-colored areas) after heart attack. At far right, however, mice that were treated with an engineered, optimized ApoM protein containing S1P have better tissue recovery than untreated mice (left) and mice that were given an inactive “dud” ApoM treatment (center). Credit: Hla lab/Boston Children’s Hospital

The average human has 60,000 miles of blood vessels coursing through their body. There are a number of mechanisms the body uses to keep that vast vascular network healthy, including a tiny fat molecule, a lipid called S1P, that plays a particularly important role.

S1P receptors dot the surface of the endothelium, a layer of cells that line the inside of all the body’s blood cells. Together, these so-called endothelial cells form a barrier between the body’s circulating blood and surrounding tissue. When S1P molecules activate their receptors, it suppresses endothelial inflammation and generally helps regulate cardiovascular health.

Now, researchers led by Timothy Hla, PhD, from the Boston Children’s Hospital Vascular Biology Program, report a novel therapeutic fusion that could trigger increased S1P receptor activity and recover blood vessel health following the onset of hypertension, atherosclerosis, stroke, heart attack and other cardiovascular diseases.

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Using ultrasound to trigger on-demand, site-specific pain relief

Ultrasound being applied to agitate injected liposomes, which then release nerve blocking medication that stops pain at the site
Ultrasound triggers the release of local anesthetics from injectable liposomes. Credit: Mary O’Reilly

According to the CDC, 91 people die from opioid overdoses every day in the U.S. Here in Massachusetts, the state has an opioid-related death rate that is more than twice the national average.

“Opioid abuse is a growing problem in healthcare,” says Daniel Kohane, MD, PhD, a senior associate in critical care medicine at Boston Children’s and professor of anesthesiology at Harvard Medical School.

Now, Kohane and other scientists who are developing triggerable drug delivery systems at Boston Children’s Hospital have found a new way to non-invasively relieve pain without opioids. Their novel system uses ultrasound to trigger the release of nerve-blocking agents — injected into specific sites of the body ahead of time — when and where pain relief is needed most. A paper describing the findings was published online today in Nature Biomedical Engineering.

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Nerve-growth agent could treat incontinence caused by spinal cord injury

Image of Rosalyn Adam, a urology researcher hoping to develop new treatments for incontinence, working in the laboratory
Rosalyn Adam is the director of urology research at Boston Children’s Hospital.

When the nerves between the brain and the spinal cord aren’t working properly, bladder control can suffer, resulting in a condition called neurogenic bladder. It’s a common complication of spinal cord injury; in fact, most people with spina bifida or spinal cord injury develop neurogenic bladders. Spontaneous activity of the smooth muscle in the wall of the bladder — called the detrusor muscle — commonly causes urine leakage and incontinence in people with neurogenic bladders.

“For children and adults, incontinence can be one of the most socially and psychologically detrimental complications of spinal cord injury,” says Rosalyn Adam, PhD, who is director of urology research at Boston Children’s Hospital. “The ultimate goal of our research is to return bladder control to the millions of Americans with neurogenic bladders.”

Now, Adam and a team of researchers think that they may have found a practical way to treat neurogenic detrusor overactivity by delivering medication directly into the bladder through self-catheterization, a practice that many people with neurogenic bladders already need to perform regularly.

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Another microbiome perspective: The host holds the leash

Abstract depiction of the microbiome

Most scientists and clinicians accept that the human microbiome impacts a person’s nutrition, immune system function, physical health and perhaps even mental illness, but exactly how or why is not well understood. Now, taking an evolutionary approach, a Boston Children’s Hospital infectious disease researcher suggests the host may play a more active role in controlling the microbiome than previously appreciated.

“I think we need to re-evaluate the way in which we think about the microbiome,” says Seth Rakoff-Nahoum, MD, PhD, a physician-scientist at Boston Children’s in the Divisions of Infectious Diseases and Gastroenterology, whose perspective was published today in Nature.

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Severe flu infections linked to underlying genetic variation

Flu virusesThe Center for Disease Control estimates that influenza virus–related illnesses account for more than 200,000 U.S. hospitalizations and 12,000 deaths annually. Young children, the elderly and people with respiratory, cardiac and other chronic health conditions are at particularly high risk for being hospitalized for influenza-related complications. Until now, there has not been a clear reason to explain why some individuals become severely ill from flu and not others.

New findings published in Nature Medicine, however, might change that.

“We’ve identified a genetic variant that we believe may put people at risk of getting life-threatening influenza infections,” says Adrienne Randolph, MD, MSc, a senior associate in pediatric critical care medicine at the Boston Children’s Hospital.

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CRISPR enables cancer immunotherapy drug discovery

Artwork depicting cancer cells with different genes deleted by CRISPR-Cas9, performed to identify novel cancer immunotherapy targets
These cancer cells (colored shapes) each have a different gene deleted through CRISPR-Cas9 technology. In a novel genetic screening approach, the T cells (red) destroy those cancer cells that have lost genes essential for evading immune attack, revealing potential drug targets for enhancing PD-1-checkpoint-based cancer immunotherapy. Credit: Haining Lab 

A novel screening method using CRISPR-Cas9 genome editing technology has revealed new drug targets that could potentially enhance the effectiveness of PD-1 checkpoint inhibitors, a promising new class of cancer immunotherapy.

The method, developed by a team at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, uses CRISPR-Cas9 to systematically delete thousands of tumor genes to test their function in a mouse model. In findings published today by Nature, researchers led by pediatric oncologist W. Nick Haining, BM, BCh report that deletion of one gene, Ptpn2, made tumor cells more susceptible to PD-1 checkpoint inhibitors. Other novel drug targets are likely around the corner.

PD-1 inhibition “releases the brakes” on immune cells, enabling them to locate and destroy cancer cells. But for many patients, it’s not effective enough on its own.

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SIDS associated with higher blood serotonin levels

A baby sleeping on its back, which is the safest sleeping position to prevent SIDS
The Safe to Sleep campaign has helped reduce SIDS deaths, but underlying causes for SIDS have largely remained mysterious.

Sudden infant death syndrome (SIDS) accounts for the greatest share of deaths in children between the ages of 1 and 12 months. What if a blood test could explain a third of SIDS deaths – and in the future, help prevent them? New findings by a Boston Children’s Hospital team show that an increased level of serotonin in blood serum may underpin some SIDS deaths and suggests the possibility that this biological vulnerability may one day be detected in the blood of living infants.

While there are known risk factors for SIDS — such as sleeping face-down or on soft surfaces — how and why such seemingly minor threats kill some children, and not others, remains a mystery.

“Research on the underlying pathology of SIDS is critical to further our understanding of the biological mechanisms contributing to a SIDS death,” says Robin Haynes, PhD, a researcher in the Department of Pathology at Boston Children’s Hospital.

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A new inlet to treating neurological disease

Image of brains showing red tracer dye, indicating passage of molecules through the blood-brain barrier
These brain images tell a story about the blood-brain barrier: At left, the brain before injection of red tracer dye. At center, an injection of tracer dye shows only a small amount of molecules can infiltrate the blood brain barrier. At right, a new approach for crossing the blood-brain barrier increases the tracer’s penetration into brain tissue.

The blood-brain barrier was designed by nature to protect the brain and central nervous system (CNS) from toxins and other would-be invaders in the body’s circulating blood. Made up of tightly-packed cells, the barrier allows nutrients to pass into the CNS and waste products from the brain to be flushed out, while blocking entry of harmful substances.

A dysfunctional blood-brain barrier can contribute to CNS diseases including Alzheimer’s and multiple sclerosis (MS). But, ironically, the same blood-brain barrier can keep out drugs intended to treat CNS disease. Scientists have long been seeking ways to overcome this obstacle.

Now, Timothy Hla, PhD, and members of his laboratory in the Boston Children’s Hospital Vascular Biology Program have found a way to selectively control openings in the blood brain barrier to allow passage of small drug molecules.

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A surprising new link between inflammation and mental illness — and a potential drug to protect the brain

A synapse being attacked by microglia, which causes neuropsychiatric symptoms in lupus
In the brain, a synapse (red – see diagonal “spine” across center of photo) is seen being wrapped around and attacked by immune cells called microglia (green), leading to synapse loss. Credit: Carroll lab / Boston Children’s Hospital

Up to 75 percent of patients with systemic lupus erythematosus — an incurable autoimmune disease commonly known as “lupus” —  experience neuropsychiatric symptoms.  But so far, our understanding of the mechanisms underlying lupus’ effects on the brain has remained murky.

“In general, lupus patients commonly have a broad range of neuropsychiatric symptoms, including anxiety, depression, headaches, seizures, even psychosis,” says Allison Bialas, PhD, a research fellow working in the lab of Michael Carroll, PhD, of Boston Children’s Hospital. “But their cause has not been clear — for a long time it wasn’t even appreciated that these were symptoms of the disease.”

Collectively, lupus’ neuropsychatric symptoms are known as central nervous system (CNS) lupus. Their cause has been unclear until now.

Perhaps, Bialas thought, changes in the immune systems of lupus patients were directly causing these symptoms from a pathological standpoint. Working with Carroll and other members of his lab, Bialas started out with a simple question, and soon, made a surprising finding – one that points to a potential new drug for protecting the brain from the neuropsychiatric effects of lupus and other diseases. The team has published its findings in Nature.

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Flipping the switch on tumor growth

Pictures of angiogenic tumor cells
Time-lapse imaging can reveal tell-tale changes in cellular behaviors associated with tumor growth.

Without a blood supply, a tumor can remain dormant and harmless. But new blood vessel growth from an existing vessel, a process called angiogenesis, is a hallmark of both benign and malignant tumors. During angiogenesis, blood vessels invade tumors and activate them, fueling their growth.

Now, Marsha A. Moses, PhD, who directs the Vascular Biology Program at Boston Children’s Hospital, and members of her laboratory have revealed that a specialized imaging system can detect changes in cell behaviors. These changes predict when tumors are leaving a state of dormancy and becoming more likely to grow.

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