Author: Kat J. McAlpine

To monitor health, simply trip the ‘nanoswitches’

WATCH: DNA nanoswitches change shape in the presence of biomarkers. The shape change is revealed in a process called gel electrophoresis. Credit: Wyss Institute at Harvard University

“Nanoswitches” — engineered, shape-changing strands of DNA — could shake up the way we monitor our health, according to new research. Faster, easier, cheaper and more sensitive tests based on these tools — used in the lab or at point of care — could indicate the presence of disease, infection and even genetic variabilities as subtle as a single-gene mutation.

“One critical application in both basic research and clinical practice is the detection of biomarkers in our bodies, which convey vital information about our current health,” says lead researcher Wesley Wong, PhD, of Boston Children’s Hospital Program in Cellular and Molecular Medicine (PCMM). “However, current methods tend to be either cheap and easy or highly sensitive, but generally not both.”

That’s why Wong and his team have adapted their DNA nanoswitch technology — previously demonstrated to aid drug discovery and the measure of biochemical interactions — into a new platform that they call the nanoswitch-linked immunosorbent assay (NLISA) for fast, sensitive and specific protein detection. It’s described this week in the Proceedings of the National Academy of Sciences.

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“Vampires” may have been real people with this blood disorder

Mural of Vlad the Impaler, who was accused of being a vampire. Perhaps, instead, he suffered from a blood disorder called porphyria.Porphyrias, a group of eight known blood disorders, affect the body’s molecular machinery for making heme, which is a component of the oxygen-transporting protein, hemoglobin. When heme binds with iron, it gives blood its hallmark red color.

The different genetic variations that affect heme production give rise to different clinical presentations of porphyria — including one form that may be responsible for vampire folklore.

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Landmark moment for science as the FDA approves a gene therapy for the first time

Leukemia blast cells, which could now be destroyed using a first-of-its-kind, FDA-approved gene therapy called CAR-T cell therapy
Leukemia blast cells.

Today, the Food and Drug Administration approved a gene therapy known as CAR T-cell therapy that genetically modifies a patient’s own cells to help them combat pediatric acute lymphoblastic leukemia (ALL), the most common childhood cancer. It is the first gene therapy to be approved by the FDA.

“This represents the progression of the field of gene therapy, which has been developing over the last 30 years,” says gene therapy pioneer David A. Williams, MD, who is chief scientific officer of Boston Children’s Hospital and president of the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center. “It’s a realization of what we envisioned to be molecular medicine when this research started. The vision — that we could alter cells in a way to cure disease — is now coming true.”

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An FDA-approved drug could prevent valve damage after heart attack

Losartan is shown to prevent thickening of the mitral valve after heart attack, in comparison with an untreated heart
An untreated mitral valve (left) shows much more thickening and fibrosis after heart attack than a mitral valve treated with losartan (right).

On average, one in four people who have a heart attack sustain long-lasting damage to the mitral valve, which has the important job of making sure blood pumps through the heart’s ventricles in the right direction. If the valve is damaged, the heart’s pumping efficiency is reduced and blood can flow backward, which can lead to heart failure and death.

Now, a team of collaborators from Boston Children’s Hospital, Massachusetts General Hospital and Brigham and Women’s Hospital has shown, for the first time, that it’s possible to treat and even prevent mitral valve damage after heart attack with an FDA-approved, anti-hypertension drug called losartan. Their findings are published in the Journal of the American College of Cardiology.

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Finding what fuels the “runaway train” of autoimmune diseases

Competing B cells, pictured here, produce autoantibodies that contribute to autoimmune disease
Natural selection on a small scale: Immune cells called B cells battle each other to produce the best antibody. Here, green represents the B cells that are producing the “winning” antibody, which stamp out competing B cells (other colors). Credit: Carroll lab

A newly-unveiled discovery, four years in the making, could change the way we look at autoimmune diseases and our understanding of how and why immune cells begin to attack different tissues in the body.

“Once your body’s tolerance for its own tissues is lost, the chain reaction is like a runaway train,” says Michael Carroll, PhD, of Boston Children’s Hospital and Harvard Medical School (HMS). “The immune response against your own body’s proteins, or antigens, looks exactly like it’s responding to a foreign pathogen.”

A team led by Carroll has spent years investigating mouse models of lupus to better understand the ins and outs of autoimmune diseases. Its latest findings, published in Cell, reveal that rogue B cells — immune cells that produce antibodies and program the immune system to attack certain antigens — can trigger an “override” that launches the body into an autoimmune attack. Adding insult to injury, B cells’ immune targeting instructions can rapidly expand to order an attack on additional tissue types within the body.

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“Shapeshifter” that regulates blood clotting is visually captured for the first time

GIF of VWF, which regulates blood clotting, elongating and relaxing on loop
A single molecule of von Willebrand factor is visually captured, as it elongates and relaxes in response to blood flow conditions, for the very first time. Credit: Springer/Wong labs (Boston Children’s Hospital and Harvard Medical School)

We are normally born with a highly sophisticated array of molecules that act as “sentries,” constantly scanning our bodies for injuries such as cuts and bruises. One such molecular sentry, known as von Willebrand factor (VWF), plays a critical role in our body’s ability to stop bleeding.

To prevent hemorrhage or life-threatening blood clots, VWF must strike a delicate balance between clotting too little or too much. Researchers have long suspected that the mechanical forces and shear stress of blood flow could be closely-related to VWF’s function.

“In some ways, like in the movie Star Wars, VWF may be considered a Jedi knight in our body that can use ‘the force’ to guard the bloodstream,” says Timothy Springer, PhD, of Boston Children’s Hospital and Harvard Medical School (HMS).

It has not been possible to witness exactly how VWF senses and harnesses these mechanical forces — until now.

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Making leaps and bounds in 10 years of genome-wide association studies

A Broad Institute cartoon explains what SNPs have to do with genome-wide association studies
A clip from a Broad Institute infographic explains what researchers look for during genome-wide association studies. Download full infographic here. Credit: Susanna Hamilton/Karen Zusi of the Broad Institute.

In 2007, when the first genome-wide association studies (GWAS) got underway, researchers began to realize just how poorly they had previously been able to predict which genes might be related to certain diseases.

“I think we were all surprised how bad our candidate gene lists were,” said Joel Hirschhorn, MD, PhD, in a recent podcast with the Broad Institute of MIT and Harvard. Hirschhorn, a pioneer in GWAS, now leads the international Genetic Investigation of Anthropometric Traits (GIANT) Consortium, which has analyzed the genomes of hundreds of thousands of people over the last several years.

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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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