The human body’s innate immune system employs a variety of “sensors” for identifying foreign invaders such as viruses. One such viral sensor is a receptor called MDA5, found in every cell of the body.
Inside each cell, MDA5 constantly scans genetic material, checking if it’s native to the body or not. As soon as MDA5 identifies the genetic signature of a viral invader, it trips a system-wide alarm, triggering a cascade of immune activity to neutralize the threat.
But if a genetic mutation to MDA5 causes it to confuse some of the body’s own genetic material for being foreign, “false alarms” can lead to unchecked inflammation and disease. Scientists from Boston Children’s Hospital have discovered a new link between MDA5’s ability to discriminate between “self” and “non-self” genetic material — called RNA duplexes — and a spectrum of autoimmune disorders. …
Boston Children’s Hospital is now enrolling patients age 3 to 35 in a clinical trial of gene therapy for sickle cell disease. Based on technology developed its own labs, it differs from other gene therapy approaches by having a two-pronged action. It represses production of the mutated beta hemoglobin that causes red blood cells to form the stiff “sickle” shapes that block up blood vessels. It also increases production of the fetal form of hemoglobin, which people normally stop making after birth.
Fetal hemoglobin doesn’t sickle and works fine for oxygen transport. The gene therapy being tested now restores fetal hemoglobin production by turning “off” a silencing gene called BCH11A.
“BCL11A represses fetal hemoglobin and also activates beta hemoglobin, which is affected by the sickle-cell mutation,” David Williams, MD, the trial’s principal investigator, told Vector last year. Williams is also president of the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center. “So when you knock BCL11A down, you simultaneously increase fetal hemoglobin and repress sickling hemoglobin, which is why we think this is the best approach to gene therapy in this disease.”
The therapy is the product of multiple discoveries, the first dating back 70 years. Click selected images below to enlarge. …
Medical devices for children tend to have small markets, so development can lag up to a decade behind similar devices for adults. The Boston Pediatric Device Consortium (BPDC), formed through an FDA initiative, aims to change that math.
This month, the BPDC and the Innovation and Digital Health Accelerator at Boston Children’s Hospital announced five winners of a national pediatric device challenge. Each winner will receive a combination of up to $50,000 in funding per grant award and/or in-kind support from leading medical device strategic partners, including Boston Scientific, CryoLife, Edwards Lifesciences, Health Advances, Johnson & Johnson Innovation, Medtronic, Smithwise, Ximedica and the Boston Children’s Simulator Program. These organizations will provide mentorship, product manufacturing and design services, simulation testing, business plan development, partnering opportunities and more.
“We have a major unmet need for pediatric medical devices that are specifically designed to address the demands of a growing, active child,” said BPDC leader Pedro del Nido, MD, chief of Cardiac Surgery at Boston Children’s, in a press release. “We are pleased to support these teams as they work toward accelerating their technologies from concept to market.”
Enterococci are hardy microbes that thrive in the gastrointestinal tracts of nearly all land animals, including our own, and generally cause no harm. But their ruggedness has lately made them leading causes of multi-drug-resistant infections, especially in settings like hospitals where antibiotic use disrupts the natural balance of intestinal microbes.
So the discovery of a new toxin in a strain of Enterococcus is raising scientific eyebrows. Isolated from cow feces sampled at a South Carolina farm, the bug was unexpectedly found to carry a toxin resembling the toxin that causes botulism. The finding was reported this week in the journal Cell Host and Microbe.
“This is the first time a botulinum neurotoxin has been found outside of Clostridium botulinum — and not just the toxin, but an entire unit containing the toxin and associated proteins that prevent the toxin from being degraded in the GI tract,” says Min Dong, PhD, a scientist in Boston Children’s Hospital’s Department of Urology and Harvard Medical School and one of the world’s experts on botulinum toxins. …
Screening a class of recently-developed drug compounds — so-called “CDK inhibitors” capable of blocking CDK7/12/13 proteins — against hundreds of different human cancer cell lines, researchers at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center have found that CDK12 inhibitors pack a particularly lethal punch to Ewing sarcoma, a rare cancer typically affecting children and young adults.
Some individuals were entirely cured of the disease
“Now, in mice, we’ve shown that Ewing sarcoma cells die if CDK12 is knocked out genetically or chemically inhibited,” Stegmaier says. What’s more, her team has discovered that CDK12 inhibition can be combined with another drug, called a PARP inhibitor, to double down on Ewing sarcoma cells.
The revelation that CDK12 inhibition can kill Ewing sarcoma cells brings a surge of hope to the field of pediatric oncology, which has long been challenged to find new drugs against childhood cancers. …
Babies’ brains are like sponges — highly tuned to incoming sensory information and readily rewiring their circuits. But when so-called critical periods close, our brains lose much of this plasticity. Classic experiments reveal this in the visual system: when kittens and mice had one eye covered shortly after birth, that eye was blind for life, even after the covering was removed. The brain never learned to interpret the visual inputs.
In 2010, a study led by Takao Hensch, PhD, of the F.M. Kirby Neurobiology Center at Boston Children’s Hospital, showed that levels of a protein called Lynx1 rise just as the critical period for visual acuity closes. When the researchers deleted the Lynx1 gene in mice, the critical period reopened and mice recovered vision in the blind eye.
Hematopoietic stem cells (HSCs) have long been regarded as the granddaddy of all blood cells. After we’re born, these multipotent cells give rise to all our cell lineages: lymphoid, myeloid and erythroid cells. Hematologists have long focused on capturing HSCs’ emergence in the embryo, hoping to recreate the process in the lab to provide a source of therapeutic blood cells.
But in the embryo, oddly enough, blood development unfolds differently. The first blood cells to show up are already partly differentiated. These so-called “committed progenitors” give rise only to erythroid and myeloid cells — not lymphoid cells like the immune system’s B and T lymphocytes.
Researchers in the lab of George Q. Daley, MD, PhD, part of Boston Children’s Hospital’s Stem Cell Research program, wanted to know why. Does nature deliberately suppress blood cell multipotency in early embryonic development? And could this offer clues about how to reinstate multipotency and more readily generate different blood cell types? …
Yes, some obesity is due to genetics. The largest and most powerful study to date has pinned down 14 variants in 13 genes that carry variations associated with body mass index. They provide new clues as to why some people tend to gain weight and have more trouble losing it. Eight of the variants were in genes not previously tied to human obesity.
The study, published last month, was conducted by the Genetic Investigation of Anthropometric Traits (GIANT) consortium, an international collaboration involving more than 250 research institutions — the same group that brought us height-related genes last year. It combined genetic data from more than 700,000 people and 125 different studies to find rare or low-frequency genetic variants that tracked with obesity.
The study focused on rarer variants in the coding portions of genes, which helped pinpoint causal genes and also helped discover variants with larger effects that those previously discovered by the GIANT consortium. For example, carriers of a variant in the gene MC4R (which produces a protein that tells the brain to stop eating and to burn more energy) weigh 15 pounds more, on average, than people without the variant.
Computational analysis provided some interesting insights into what the 13 genes do. Some, for example, play a role in brain pathways that affect food intake, hunger and satiety. Other variants affect fat-cell biology and how cells expend energy.
“This study provided an important confirmation of the role of the nervous system in body weight regulation,” says Joel Hirschhorn MD, PhD, a pediatric endocrinologist and researcher at Boston Children’s Hospital and the Broad Institute of MIT and Harvard, who co-led the study with Ruth Loos, PhD, of the Icahn School of Medicine at Mount Sinai. “Many of the genes from this study were not known to be associated with obesity, but our computational analysis independently implicates these new genes in strikingly similar neuronal pathways as the genes that emerged from our previous work. In addition, our approach newly highlighted a role for genes known to be important in ‘brown fat,’ a type of fat that burns energy and may help keep people lean.”
The researchers think the new findings could help focus the search for new therapeutic targets in obesity. Read more in Nature Genetics and this press release from Mount Sinai.
Researchers have discovered that killing cancer cells can actually have the unintended effect of fueling the proliferation of residual, living cancer cells, ultimately leading to aggressive tumor progression.
In their study, published in the January issue of the Journal of Experimental Medicine, the researchers describe how chemotherapy or other targeted therapies create a build-up of tumor cell debris, comprised of dead, fragmented cancer cells. In animal models, the team observed that this cell debris sets off an inflammatory cascade in the body and also encourages lingering, living cancer cells to develop into new tumors.
“Our findings reveal that conventional cancer therapy is essentially a double-edged sword,” says co-senior author on the study Mark Kieran, MD, PhD, who directs the Pediatric Brain Tumor Program at Dana-Farber/Boston Children’s and is an associate professor of pediatrics at Harvard Medical School. “But more importantly, we also found a pathway to block the tumor-stimulating effects of cancer cell debris — using a class of mediators called resolvins.” …