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.

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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.

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News Note: Norovirus outbreak threatens the Olympics

The HealthMap team at Boston Children's is currently tracking norovirus at the Olympics
The Computational Epidemiology Team at Boston Children’s Hospital tracks online, informal sources for disease outbreak monitoring and real-time surveillance of emerging public health threats through a platform called HealthMap. This is an image of what their surveillance dashboard is currently tracking (Feb. 15, 2018) in South Korea. Visit http://www.healthmap.org/en/ for more.

The 2018 Winter Olympics have brought nearly 3,000 delegates from 206 countries together in PyeongChang, South Korea. But just a week after kicking off on February 8, the games and its attendees are already being interrupted by a fast-spreading norovirus outbreak.

Norovirus is an extremely infectious disease transmitted through food, water or by touching a contaminated surface. Infection causes inflammation of the stomach and intestines, which can lead to symptoms including stomach pains, nausea, vomiting and diarrhea.

In PyeongChang, there have already been 199 confirmed cases of norovirus — many of those sickened have been security guards hired for the games. Due to severe gastrointestinal symptoms, 41 guards have been hospitalized and more than 1,200 were placed in quarantine. 

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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.

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Breaking down brain disease one DNA break at a time

DNA breaks are depicted in this artistic renderingCells throughout the human body are constantly being damaged as a part of natural life, normal cellular processes, UV and chemical exposure and environmental factors — resulting in what are called DNA double-strand breaks. Thankfully, to prevent the accumulation of DNA damage that could eventually lead to cell dysfunction, cancer or death, the healthy human body has developed ways of locating and repairing the damage.

Unfortunately, these DNA repair mechanisms themselves are not impervious to genetic errors. Genetic mutations that disrupt DNA repair can contribute to devastating disease.

Across the early-stage progenitor cells that give rise to the human brain’s 80 billion neuronal cells, genomic alterations impacting DNA repair processes have been linked to neuropsychiatric disorders and the childhood brain cancer medulloblastoma. But until now, it was not known exactly which disruptions in DNA repair were involved.

A Boston Children’s Hospital team led by Frederick Alt, PhD, has finally changed that.

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Single-shot protection? Building a better hepatitis B vaccine for newborns

newborn vaccines
(Illustrations: Elena Hartley)

The hepatitis B vaccine is one of only three vaccines that are routinely given to newborns in the first days of life. But the current hepatitis B vaccine has limitations: multiple “booster” doses are needed, and it can’t be given to premature babies weighing less than 2 kg.

Annette Scheid, MD, a neonatologist at Brigham and Women’s Hospital, is interested in leveraging infant immune differences to create a better hepatitis B vaccine for newborns. “The reality is that we have to vaccinate several times,” she says. “But we all dream of a vaccine that you give only once.”

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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.”

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Link found between chronic inflammation, autoimmune disorders and “false alarms”

Viruses (pictured here) have a genetic signature that a receptor called MDA5 recognizes. But when MDA5 confuses the body's own genetic material with that of a virus, disease ensues.
Viruses have a genetic signature that a human receptor called MDA5 recognizes, causing the immune system to attack. But when MDA5 confuses the body’s own genetic material for that of a virus, disease ensues.

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.

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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.

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Digital doctoring, big data and AI: Five takeaways

digital health

Big data and artificial intelligence are reshaping our world. Earlier this month, at Computefest 2018, organized by the Institute for Applied Computational Science at Harvard University, held the symposium, “The Digital Doctor: Health Care in an Age of AI and Big Data.” Speakers were:

  • Finale Doshi-Velez, PhD, Assistant Professor of Computer Science, Harvard University
  • Matt Might, Director, Hugh Kaul Personalized Medicine Institute, University of Alabama at Birmingham
  • John Brownstein, PhD, Chief Innovation Officer and Director, Computational Epidemiology Lab, Boston Children’s Hospital
  • Marzyeh Ghassemi, PhD, Visiting Researcher, Google’s Verily; Postdoctoral Fellow, Computer Science and Artificial Intelligence Lab, Massachusetts Institute of Technology
  • Jennifer Chayes, Managing Director, Microsoft Research New England and New York City
  • Emery Brown, PhD, Professor of Medical Engineering and Computational Neuroscience, Massachusetts Institute of Technology

Here are Vector’s five takeaways from the symposium:

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