Stories about: Science

A breakthrough in our understanding of how red blood cells develop

Artist's rendering of red blood cells
Red blood cells.

By taking a deep dive into the molecular underpinnings of Diamond-Blackfan anemia, scientists have made a new discovery about what drives the development of mature red blood cells from the earliest form of blood cells, called hematopoietic (blood-forming) stem cells.

For the first time, cellular machines called ribosomes — which create proteins in every cell of the body — have been linked to blood stem cell differentiation. The findings, published today in Cell, have revealed a potential new therapeutic pathway to treat Diamond-Blackfan anemia. They also cap off a research effort at Boston Children’s Hospital spanning nearly 80 years and several generations of scientists.

Diamond-Blackfan anemia — a severe, rare, congenital blood disorder — was first described in 1938 by Louis Diamond, MD, and Kenneth Blackfan, MD, of Boston Children’s. The disorder impairs red blood cell production, impacting delivery of oxygen throughout the body and causing anemia. Forty years ago, David Nathan, MD, of Boston Children’s determined that the disorder specifically affects the way blood stem cells become mature red blood cells.

Then, nearly 30 years ago, Stuart Orkin, MD, also of Boston Children’s, identified a protein called GATA1 as being a key factor in the production of hemoglobin, the essential protein in red blood cells that is responsible for transporting oxygen. Interestingly, in more recent years, genetic analysis has revealed that some patients with Diamond-Blackfan have mutations that block normal GATA1 production.

Now, the final pieces of the puzzle — what causes Diamond-Blackfan anemia on a molecular level and how exactly ribosomes and GATA1 are involved — have finally been solved by another member of the Boston Children’s scientific community, Vijay Sankaran, MD, PhD, senior author of the new Cell paper.

Read Full Story | Leave a Comment

Science Seen: Imaging early auditory brain development

Auditory brain development - Heschl’s gyrus at 28 and 40 weeks
Copyright © 2018 Monson et al.

Babies can hear and respond to sounds, including language, before birth. In fact, research shows that babies learn to recognize words in the womb. Now, an advanced MRI technique called diffusion tensor imaging is providing a fine-tuned view of when different brain areas mature, including the areas that process sound. And the findings suggest that babies born prematurely may have disruptions in auditory brain development and in speech.

Investigators at Boston Children’s Hospital, Brigham and Women’s Hospital, Washington University School of Medicine in St. Louis and University College London analyzed advanced MRI brain images from 90 preterm infants and 15 infants born at full term (40 weeks). Fifty-six of the preterm infants were imaged at multiple time points. As shown above, the team focused on a particular fold in the brain called Heschl’s gyrus (HG). This area contains the primary auditory cortex, the first part of the auditory cortex to receive sound signals, and the non-primary auditory cortex, which plays a higher-level role in processing those stimuli.

As seen in these sample images, the primary cortex has largely matured at 28 weeks’ postmenstrual age (PMA), whereas the non-primary auditory cortex has had a surge in development between 28 and 40 weeks’ PMA. Both regions appeared underdeveloped in the premature infants as compared with the infants born at term.

The study further found that disturbed maturation of the non-primary cortex was associated with poorer expressive language ability at age 2. The team suggests that this area may be especially vulnerable to disruption in a premature birth because it is undergoing such rapid change.

The study was published in eNeuro, an open-access journal from the Society for Neuroscience. Jeffrey Neil, MD, PhD, of Boston Children’s Department of Neurology, was senior author on the paper. First author Brian Monson, PhD, is now at the University of Illinois at Urbana-Champaign. Read more in the university’s press release.

Read Full Story | Leave a Comment

News Note: Modeling sepsis better to find a cure faster

In this SEM image, E. coli (green) bacteria, a common instigator of sepsis, is captured by bioengineered magnetic beads.
New assessment criteria for monitoring sepsis in pig models could help clinical researchers more accurately evaluate potential sepsis treatments in preclinical experiments. In this SEM image, E. coli (green) bacteria, a common instigator of sepsis, is captured by bioengineered magnetic beads. Credit: Wyss Institute at Harvard University

Sepsis, or blood poisoning, occurs when the body’s response to infection damages its own tissues, leading to organ failure. It is the most common cause of death in people who have been hospitalized, yet no new therapies have been developed in the last 30 years. Many treatments that have prevented death in animal experiments have failed in clinical trials, indicating that a more clinically-relevant sepsis model is needed for therapeutic development.

To bridge this gap, a team of scientists from the Wyss Institute at Harvard University and Boston Children’s Hospital think a better experimental model of sepsis in pigs could help weed out the therapies most likely to succeed in humans. Their method, a scoring criteria to evaluate sepsis in pigs that closely mirrors standard human clinical assessment, is reported in Advances in Critical Care Medicine.

Read Full Story | Leave a Comment

This autoimmune awareness month, meet Boston scientists who are pushing the envelope in autoimmune research

“Red” and “green” B cells emerge from the pack as best producers of the potent autoantibodies in a mouse model of the autoimmune disease known as lupus.
In a mouse model of lupus, colorized red and green B cells outdo their blue, yellow and aqua competitors. Each color represents a different B cell clone. The proliferation of red and green B cells demonstrates that these clones have emerged as the best producers of autoantibodies. Credit: Michael Carroll lab (Boston Children’s Hospital/Harvard Medical School)

The basic biological mechanisms that underpin autoimmune disorders are finally coming to light. Researchers in Boston’s Longwood medical area — a neighborhood where the streets are flanked by hospitals, research institutions and academic centers — are setting the stage for a new wave of future therapies that can prevent, reduce or even reverse symptoms of disease.

Inside the lab of Michael Carroll, PhD, scientists are working to understand how and why immune cells start to attack the body’s own tissues; it turns out the immune system’s B cells compete with each other in true Darwinian fashion. On the way to this discovery, the lab has flushed out new potential drug targets that could ease autoimmune symptoms — or stop them entirely — by “resetting” the body’s tolerance to itself.

Carroll’s team has also drawn some of the first links between chronic inflammation, synapse loss and neuropsychiatric disease in lupus.

The implications for a link between inflammation and synapse loss go beyond lupus because inflammation underpins so many diseases and conditions, ranging from Alzheimer’s to viral infection and even to to chronic stress. In which case, are we all losing synapses to some varying degree? Carroll plans to find out.

Meanwhile, Sun Hur, PhD, and members of her lab are digging deep on a genetic variant and its link to pediatric inflammatory autoimmune disorders like Aicardi-Goutieres syndrome.

“We’ve found that chronic inflammation and autoinflammatory disorders can originate from genetic mutations to MDA5 that cause it to misrecognize ‘self’ as ‘non-self,’ essentially launching the immune system into self-attack mode,” said Hur.

Read Full Story | Leave a Comment

A new tactic for eczema? A newly identified brake on the allergic attack

baby with eczema
(Arkady Chubykin/Adobe Stock)

Eczema affects about 17 percent of children in developed countries. Often, it’s a gateway to food allergy and asthma, initiating an “atopic march” toward broader allergic sensitization. There are treatments – steroid creams and a recently approved biologic – but they are expensive or have side effects. A new study in Science Immunology suggests a different approach to eczema, one that stimulates a natural brake on the allergic attack.

The skin inflammation of eczema is known to be driven by “type 2” immune responses. These are led by activated T helper 2 (TH2) cells and type 2 innate lymphoid cells (ILC2s), together known as effector cells. Another group of T cells, known as regulatory T cells or Tregs, are known to temper type 2 responses, thereby suppressing the allergic response.

Yet, if you examine an eczema lesion, the numbers of Tregs are unchanged. Interestingly, Tregs comprise only about 5 percent of the body’s T cells, but up to 50 percent of T cells in the skin.

Read Full Story | Leave a Comment

Snaps from the lab: From gene discovery to gene therapy for one rare disease

Will Ward’s birthday falls on Rare Disease Day (Feb. 28). That’s an interesting coincidence because he has a rare disease: X-linked myotubular myopathy (MTM), a rare, muscle-weakening disease that affects only boys. Originally on Snapchat, this video captures the Ward family’s recent visit to the lab of Alan Beggs, PhD to learn more about MTM research.

Beggs, director of the Manton Center for Orphan Disease Research at Boston Children’s Hospital, has known Will since he was a newborn in intensive care. In this lab walk-though you’ll see a freezer filled with muscle samples, stored in liquid nitrogen; muscle tissue under a microscope; gene sequencing to identify mutations causing MTM and other congenital myopathies and a testing station to measure muscle function in samples taken from animal models.

Beggs’s work, which began more than 20 years ago, led to pivotal studies in male Labrador retrievers who happen to have the same mutation and are born with a canine form of MTM. By adding back a healthy copy of the gene, Beggs’s collaborators got the dogs back on their feet running around again. (Read about Nibs, a female MTM carrier whose descendants took part in these studies.)

Based on the canine results, a clinical trial is now testing gene therapy in boys under the age of 5 with MTM. The phase I/II trial aims to enroll 12 boys and measure their respiratory and motor function and muscle structure after being dosed with a vector carrying a corrected MTM gene. In the meantime, observational and retrospective studies are characterizing the natural history of boys with MTM.

Learn more about the Manton Center for Orphan Disease Research.

Read Full Story | Leave a Comment

Maintaining mitochondria in neurons: A new lens for neurodegenerative disorders

cartoon of mitochondria being transported in neurons - part of mitostasis
In some neurons, mitochondria must travel several feet along an axon. (Elena Hartley illustration)

Tom Schwarz, PhD, is a neuroscientist at Boston Children’s Hospital’s F.M. Kirby Neurobiology Center, focusing on the cell biology of neurons. Tess Joosse is a biology major at Oberlin College. This article is condensed from a recent review article by Schwarz and Thomas Misgeld (Technical University of Munich).

Like all cells, the neurons of our nervous system depend on mitochondria to generate energy. Mitochondria need constant rejuvenation and turnover, and that’s especially true in neurons because of their high energy needs for signaling and “firing.” Mitochondria are especially abundant at presynaptic sites — the tips of axons that form synapses or junctions with other neurons and release neurotransmitters.

But the process of maintaining mitochondrial number and quality, known as mitostasis, also poses particular challenges in neurons. Increasingly, mitostasis is providing a helpful lens for understanding neurodegenerative disorders. Problems with mitostasis are implicated in Parkinson’s disease, Alzheimer’s disease, ALS, autism, stroke, multiple sclerosis, hypoxia and more.

Read Full Story | Leave a Comment

Lab-grown human cerebellar cells yield clues to autism

This Purkinje cell, made from a patient with tuberous sclerosis, will enable study of autism disorders. (Credit: Maria Sundberg)

Autism spectrum disorder (ASD) is increasingly linked with dysfunction of the cerebellum, but the details, to date, have been murky. Now, a rare genetic syndrome known as tuberous sclerosis complex (TSC) is providing a glimpse.

TSC includes features of ASD in about half of all cases. Previous brain autopsies have shown that patients with TSC, as well as patients with ASD in general, have reduced numbers of Purkinje cells, the main type of neuron that communicates out of the cerebellum.

In a 2012 mouse study, team led by Mustafa Sahin, MD, at Boston Children’s Hospital, knocked out a TSC gene (Tsc1) in Purkinje cells. They found social deficits and repetitive behaviors in the mice, together with abnormalities in the cells.

The new study, published last week in Molecular Psychiatry, takes the research into human cells, for the first time creating cerebellar cells known as Purkinje cells from patients with TSC.

Read Full Story | Leave a Comment

Intestine chip models gut function, in disease and in health

villus-like projections growing in gut chip
Villus-like extensions formed by small intestinal cells from patient biopsies, protruding into the Intestine Chip’s luminal channel. (Credit: Wyss Institute at Harvard University)

The small intestine is much more than a digestive organ. It’s a major home to our microbiome, it’s a key site where mucosal immunity develops and it provides a protective barrier against a variety of infections. Animal models don’t do justice to the human intestine in all its complexity.

Attempts to better model human intestinal function began with intestinal “organoids,” created from intestinal stem cells. The cells, from human biopsy samples, form hollowed balls or “mini-intestines” bearing all the cell types of the intestinal lining, or epithelium. Recently, intestinal organoids helped reveal how Clostridium difficile causes such devastating gastrointestinal infections.

But while organoids have all the right cells, they don’t fully replicate the environment of a real small intestine. Real intestines are awash in bacteria and nutrients, are fed by blood vessels and are stretched and compressed by peristalsis, the intestines’ cyclical muscular contractions that push nutrients forward.

Efforts to recreate that environment led to the Intestine Chip. An early version, created by the Wyss Institute for Biologically Inspired Engineering, cultured cells from a human intestinal tumor cell line.

Read Full Story | Leave a Comment

Building a better bubble: Engineering tweaks bring safe IV oxygen delivery closer to reality

thin-shelled engineered oxygen bubbles
(Courtesy Yifeng Peng, Boston Children’s Hospital)

Everything from food aspiration to an asthma attack to heart failure can cause a patient to die from asphyxia, or lack of oxygen. For more than a decade, the Translational Research Laboratory (TRL) of Boston Children’s Hospital’s Heart Center has been pursuing a dream: tiny, oxygen-filled bubbles that can be safely injected directly into the blood, resuscitating patients who can’t breathe.

The lab’s first generation of bubbles were made with a fatty acid, but the lipid shells weren’t stable enough for long-term storage or clinical use. The bubbles popped open too easily.

Read Full Story | Leave a Comment