Author: Nancy Fliesler

Deconstructing neuropathic pain: Could it give clues to better drugs?

neuropathic pain

Neuropathic pain is chronic pain originating through some malfunction of the nervous system, often triggered by an injury. It causes hypersensitivity to innocuous stimuli and is often extremely debilitating. It doesn’t respond to existing painkillers — even opioids can’t reach it well.

New research in a mouse model, described last week in Cell Reports, deconstructed neuropathic pain and could offer new leads for treating it. The carefully done study showed that two major neuropathic pain symptoms in patients — extreme touch sensitivity and extreme cold sensitivity — operate through separate pathways.

“We think this separation will allow targeted drug-based therapies in the future,” says Michael Costigan, PhD, of the F.M. Kirby Neurobiology Center at Boston Children’s Hospital, who was the study’s senior investigator. “If our results stand experimental scrutiny by others, this will be profoundly important in our overall understanding of neuropathic pain.”

Read Full Story | Leave a Comment

Sickle cell gene therapy to boost fetal hemoglobin: A 70-year timeline of discovery

sickled cells occluding a blood vessel
Sickled cells occluding a blood vessel. (Image: Elena Hartley)

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.

Read Full Story | Leave a Comment

Five devices for pediatrics get help in advancing to market

kids with pediatric devices playing doctor

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.”

The five Challenge winners are:

Read Full Story | Leave a Comment

Botulinum-type toxins jump to a new kind of bacteria. Should we sound an alarm?

(Illustration: Elena Hartley)

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.

Read Full Story | Leave a Comment

Opening up brain critical periods: Lynx1 and where sensory information meets context

auditory critical periods involve neurons in levels 1 and 4 of the auditory cortex
Interneurons (white) from layer 1 (L1) of the auditory cortex descend to contact parvalbumin cells (red) in layer 4. (Images courtesy Hensch Lab).

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.

A new study this week in Nature Neuroscience extends Lynx1’s role to the auditory system.

“If we remove Lynx1, the auditory critical period stays open longer,” says Hensch.

Equally important, the study pinpoints the location in the brain where sensory inputs combine with another essential ingredient: what neuroscientists call context.

Read Full Story | Leave a Comment

More surprises about blood development — and a possible lead for making lymphocytes

blood development chart
Blood development in the embryo begins with cells that make myeloid and erythroid cells – but not lymphoid cells. Why? A partial answer is in today’s Nature.

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?

Read Full Story | Leave a Comment

News note: GIANT study homes in on obesity genes

obesity genes
Illustration: Elena Hartley

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.

Read Full Story | Leave a Comment

‘Pull’ from an implanted robot could help grow stunted organs

Surgeons at Boston Children’s Hospital have long sought a better solution for long-gap esophageal atresia, a rare birth defect in which part of the esophagus is missing. The current state-of-the art operation, called the Foker process, uses sutures anchored to children’s backs to gradually pull the unjoined ends of esophagus until they’re long enough to be stitched together. To keep the esophagus from tearing, children must be paralyzed in a medically induced coma, on mechanical ventilation, for one to four weeks. The lengthy ICU care means high costs, and the long period of immobilization can cause complications like bone fractures and blood clots.

Now, a Boston Children’s Hospital team has created an implantable robot that could lengthen the esophagus — and potentially other tubular organs like the intestine — while the child remains awake and mobile. As described today in Science Roboticsthe device is attached only to the tissue being lengthened, so wouldn’t impede a child’s movement.

Read Full Story | Leave a Comment

News Note: Cell ‘barcodes’ trace the natural development of blood

in situ blood development
(Credit: Stem Cell Program, Boston Children’s Hospital)

Genetic labels, or “barcodes,” are shedding new light on the natural process of blood development and immune-cell production, finds a study published in Nature this week. It was led by Fernando Camargo, PhD, and first author Alejo Rodriguez Fraticelli, PhD, at Boston Children’s Hospital’s Stem Cell Research Program, the Harvard Department of Stem Cell and Regenerative Biology and the Harvard Stem Cell Institute.

Most of what we know about blood production is through observing what happens when blood stem and progenitor cells are transplanted into an animal. To observe what happens “in the wild,” researchers went in and tagged the blood stem and progenitor cells of mice, using genetic elements called transposons. This allowed them to track how the cells differentiated into five kinds of blood cells (above: megakaryocytes, erythroid cells, granulocytes, monocytes and B-cell progenitors).

Read Full Story | Leave a Comment

News Note: More evidence that high-glycemic diets cause obesity

a high-glycemic diet

A large genetic analysis lends credence to the idea that insulin spikes after eating high-glycemic foods promote weight gain. People genetically predisposed to produce higher than normal levels of insulin after eating processed carbohydrates — “bad carbs” like white bread, potatoes and refined sugar — were more likely to be obese, the study found.

The researchers, led by David Ludwig, MD, PhD, of Boston Children’s Hospital, Joel Hirschhorn, MD, PhD, of Boston Children’s and the Broad Institute, and Jose Florez, MD, PhD, of the Broad Institute and Massachusetts General Hospital, tapped a collection of large-scale genome-wide association studies. Analyzing data from more than 26,000 people who had glucose challenges, they identified genetic variants linked with high insulin levels 30 minutes after the challenge.

Read Full Story | Leave a Comment