Immune gene guards against type 1 diabetes by changing the microbiome. Do early antibiotics undercut its effects?

type 1 diabetes microbiome antibiotics

The health of our immune system is increasingly linked with the health of our intestinal bacteria. A mouse study from Harvard Medical School now hammers this home for autoimmune disorders, in which the body attacks its own cells. It looked specifically at type 1 diabetes, in which the body destroys the cells that make insulin.

Scientists have long known that the human leukocyte antigen (HLA) complex of proteins (also known as the major histocompatibility complex, or MHC) keep autoimmune responses in check. Certain common variants of the HLA/MHC genes are known to protect against a type 1 diabetes. But until now, how these genes prevent autoimmune reactions has been a mystery.

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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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Galloway-Mowat mutations have dual target: kidney cells, neurons

Evidence of disease in GAMOS patients
Disease phenotype of GAMOS patients. Left: Kidney cells show signs of nephrotic syndrome. Right: Anomalies in brain development

With the help of more than 100 clinical collaborators around the world, Friedhelm Hildebrandt, MD has received thousands of blood samples from patients with nephrotic syndrome. They have helped Hildebrandt’s lab determine several underlying causes of this serious kidney disorder, in which high levels of protein are expelled in the urine.

“Nephrotic syndrome is not one disease; in fact, we already know that it is 55 different diseases,” says Hildebrandt, chief of the Division of Nephrology at Boston Children’s Hospital.

Over the course of time, Hildebrandt’s lab has discovered 35 of the more than 55 genes that can cause nephrotic syndrome. Identifying the different genetic pieces of the puzzle can help tailor a precision medicine approach to treating patients.

The latest piece, published earlier this month in Nature Genetics, is a set of four single-gene mutations that cause Galloway-Mowat syndrome (GAMOS) a rare disorder causing early-onset nephrotic syndrome and, often, microcephaly (abnormally small head size). Until now, the genetic changes underlying GAMOS and why they affect two disparate organs — the brain and kidney — have not been well understood. 

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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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“Omics” study takes a comprehensive look at premature birth

Seven layers of omics study
Seven layers of “omics” included in the PREM-MAP study

Every year, one in 10 new babies in the United States is born preterm, or before 37 weeks of gestation. With the last few weeks of pregnancy crucial to proper development of the lungs and brain, prematurely born infants can suffer lifelong problems.

Now scientists at Boston Children’s Hospital and Beth Israel Deaconess Medical Center have launched a comprehensive study to understand the reasons and risk factors for premature births. Earlier this year, Olaf Bodamer, MD, PhD was awarded a grant for this work from uBiome, a microbial genomics company.

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A metabolic treatment for pancreatic cancer?

nitrogen disposal is important to pancreatic cancer
Targeting an enzyme that helps dispose of excess nitrogen curbed malignant growth of pancreatic tumors in obese mice.

Pancreatic cancer has become the third leading cause of cancer mortality. Its incidence is rising in parallel with the rise in obesity, and it’s hard to treat: five-year survival still hovers at just 8 to 9 percent. A new study published online in Nature Communications finds early success with a completely new, metabolic approach: reducing tumors’ ability to get rid of excess nitrogen.

The researchers, led by Nada Kalaany, PhD, of Boston Children’s Hospital’s Division of Endocrinology and the Broad Institute of MIT and Harvard, provide evidence that targeting the enzyme arginase 2 (ARG2) can curb pancreatic tumor growth, especially in people who are obese.

“We found that highly malignant pancreatic tumors are very dependent on the nitrogen metabolism pathway,” says Kalaany.

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Novel therapeutic cocktail could restore fine motor skills after spinal cord injury and stroke

CST axons sprout from intact to injured side
Therapeutic mixture induces sprouting of axons from healthy (L) into the injured (R) side of the spinal cord.

Neuron cells have long finger-like structures, called axons, that extend outward to conduct impulses and transmit information to other neurons and muscle fibers. After spinal cord injury or stroke, axons originating in the brain’s cortex and along the spinal cord become damaged, disrupting motor skills. Now, reported today in Neuron, a team of scientists at Boston Children’s Hospital has developed a method to promote axon regrowth after injury.

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