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.

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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.

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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.

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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.

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Giving voice a voice in health care

voice technology in healthcare

Physicians, like consumers in general, are increasingly embracing voice technology and smart home speakers. But does voice have a role in health care itself, beyond simple dictation of clinical notes? Boston Children’s Hospital is among those experimenting. The hospital’s Innovation and Digital Health Accelerator (IDHA) describes its learnings in an article published today by Harvard Business Review.

After hosting a Voice in Healthcare hackathon in various simulated clinical environments in 2016, IDHA ran three pilots with voice-based systems. In the intensive care unit, clinicians used voice as a hands-free way to get basic information, saving time while maintaining infection control standards. The pediatric transplant team used voice prompts to guide them through the pre-operative organ-validation and checklist process.

voice technology in health care Harvard Business ReviewThe third, longest-running pilot is in patients’ homes: Through KidsMD, parents have logged more than 100,000 interactions with Amazon’s voice assistant, Alexa, receiving personalized guidance around common illnesses like ear infections, fever and the common cold. More types of wellness and disease-specific “skills” are in the works to create true home health hubs.

Voice has its limitations, but in a Boston Children’s survey, only 16% of physicians stated they would not try voice.

Read more in HBR and check out IDHA’s portfolio.


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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.

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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.

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Virtual reality tool lets kids voyage through their own bodies

HealthVoyager - stomach
Traditionally, doctors share the findings of invasive tests using printouts that are highly text-based and filled with medical jargon. Some may have static thumbnail illustrations, but all in all they’re not especially patient friendly.

Michael Docktor, MD, a pediatric gastroenterologist at Boston Children’s Hospital, believed that if kids could really “see” inside themselves, they would have a better understanding of their disease and be more engaged in their treatment.

He connected with Klick Health, a health marketing and commercialization agency that develops digital solutions. Together, they created an entertaining “virtual reality” educational experience. It allows the physician to easily recreate a patient’s actual endoscopic procedure, and, like the Magic School Bus, enables kids to virtually tour their own bodies.

Boston Children’s and Klick Health officially unveiled the iPhone-friendly VR tool, called HealthVoyagerTM, in New York today.

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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.

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News Note: Why is this eye cancer making headlines?

This illustrations shows a catheter is used during intra-arterial chemotherapy for retinoblastoma.
During intra-arterial chemotherapy for retinoblastoma, a catheter is placed into the common femoral artery and threaded through a child’s vasculature to access the blood vessel of the affected eye and deliver a concentrated dose of chemotherapy. Illustration: Dana-Farber/Boston Children’s.

Retinoblastoma is a rare cancer that originates in the retina, the tissue in the back of the eye that converts light into visual information that is interpreted by the brain.

One retinoblastoma symptom in particular is finding itself in the spotlight. With a rise in social media use in recent years, retinoblastoma has attracted media attention for being a type of cancer that can sometimes be detected through photographs. Across the internet, news stories like this one abound in which friends or relatives have alerted parents to the potential risk of eye cancer after noticing that a child’s pupil appears white instead of red — a symptom called leukocoria — on photos posted to social media.

Fortunately, with proper diagnosis and treatment, 95 percent of children diagnosed with retinoblastoma can be cured. What’s more, a catheter-based treatment approach is now sparing patients from some of the side effects that can be expected from more traditional therapies.

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