Author: Nancy Fliesler

Of bugs, genes, development and intestinal biology

genes intestinal developmentThe collection of bacteria and other microorganisms living in our intestines—our microbiota—is now understood to play an important role in our physiology. Recent research indicates that it helps regulate our metabolism, immune system and other biological processes, and that imbalances in the microbiota are associated with everything from inflammatory bowel disease to diabetes.

Seth Rakoff-Nahoum, MD, PhD, wants to take this understanding to a new level. An infectious disease clinical fellow at Boston Children’s Hospital, he has systematically probed how genetics interact with environment—including the microbiota—to shape intestinal biology during different stages of development.

His investigations provide interesting clues to disorders that have their origins early in life, ranging from necrotizing enterocolitis in newborns to Hirschsprung’s disease (marked by poor intestinal motility) to food allergies.

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Epilepsy surgery: When it’s not good to wait

epilepsy surgery life expectancyAbout a third of children with epilepsy do not get better with drug treatment. Many physicians are inclined to try additional drugs to control the seizures—and there are many to choose from. However, analysis of data from tens of thousands of patients suggests that if two or more well-chosen drugs have failed, and surgery is a safe option, there’s no benefit in holding off.

The decision analysis, published in the February issue of Epilepsia, found that average life expectancy was more than five years greater when eligible children had surgery rather than prolonged drug treatment. And children spent more of their lives seizure-free.

Although clinical guidelines currently do call for earlier surgery, physicians tend to use it as a last resort—even when brain-mapping studies indicate that it’s unlikely to endanger vital brain structures.

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Can rare disease genes be protective?

Carriers of the rare disease Niemann-Pick C1 may be protected against Ebola.
Carriers of the rare disease Niemann-Pick C1 may be protected against Ebola.
First of several posts to commemorate (Feb 28, 2015).

Evolution is a strange thing: sometimes it favors keeping a mutation in the gene pool, even when a double dose of it is harmful—even fatal. Why? Because a single copy of that mutation is protective in certain situations.

A classic example is the sickle-cell mutation: People carrying a single copy don’t develop sickle cell disease, but they make enough sickled red blood cells to keep the malaria parasite from getting a toe-hold. (Certain other genetic disorders affecting red blood cells have a similar effect.)

Or consider cystic fibrosis. Carriers of mutations in the CFTR gene—some 1 in 25 people of European ancestry—appear to be protected from typhoid fever, cholera and possibly tuberculosis.

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A link between cystic fibrosis and arsenic poisoning?

boys playing in arsenic-endemic area of Bangladesh
Research in Bangladesh suggests that arsenic poisoning can cause cystic-fibrosis-like illness, quite aside from the classic genetic disease. (Photo: Nadia Shobnam)
Since its causative gene was sequenced in the 1980s, cystic fibrosis (CF) has been the “textbook” genetic disease. Several thousand mutations have been identified in the CFTR protein, which regulates the flow of chloride in and out of cells. When CFTR is lost or abnormal, thick mucus builds up, impairing patients’ lungs, liver, pancreas, and digestive and reproductive systems, and making their lungs prone to opportunistic infections.

But new research could add a chapter to the textbook, pinpointing an unexpected environmental cause of CF-like illness. A study reported in the February 5 New England Journal of Medicine found that people with arsenic poisoning have high chloride levels in their sweat—the classic diagnostic sign of CF.

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Autism-like behaviors, impaired nerve tracts found in institutionalized children

Sad child-shutterstock_92102072 croppedThe sad experience of abandoned children in Romanian orphanages continues to provide stark lessons about the effects of neglect and deprivation of social and emotional interactions. The long-running Bucharest Early Intervention Project (BEIP) has been able to transfer some of these institutionalized children, selected at random, into quality foster care homes—and documented the benefits.

In a review article in the January 29 Lancet, BEIP investigator Charles A. Nelson, PhD, and medical student Anna Berens, MsC, both of Boston Children’s Hospital, make a strong case for global deinstitutionalization—as early in a child’s life as possible. Currently, it’s estimated that at least 8 million children worldwide are growing up in institutional settings.

The BEIP studies have documented a series of problems in institutionalized children, especially those who aren’t placed in foster care or are placed when they are older:

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What we’ve been reading: Week of January 26, 2015

What we are reading 4Vector’s picks of recent pediatric healthcare, science and innovation news.

U.S. proposes effort to analyze DNA from 1 million people (Reuters)
President Obama provided more detail last week on his Precision Medicine Initiative, which would allocate $215 million toward developing treatments tailored to patients’ genetic makeup, including $70 million for cancer research. The initiative is being hailed as a shot in the arm for research and innovation (this cancer example is but one of many), but skeptics question whether precision medicine will live up to its touted potential, citing the shortcomings of genomics in determining disease risk or in reversing diseases, even when genetic variants have been well studied.

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Live imaging captures how blood stem cells take root in the body

For years, the lab of Leonard Zon, MD, director of the Stem Cell Research Program at Boston Children’s Hospital, has sought ways to enhance bone marrow transplants for patients with cancer, serious immune deficiencies and blood disorders. Using zebrafish as a drug-screening platform, the lab has found a number of promising compounds, including one called ProHema that is now in clinical trials.

But truthfully, until now, Zon and his colleagues have largely been flying blind.

“Stem cell and bone marrow transplants are still very much a black box: cells are introduced into a patient and later on we can measure recovery of their blood system, but what happens in between can’t be seen,” says Owen Tamplin, PhD, in the Zon Lab. “Now we have a system where we can actually watch that middle step.”

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Mapping mosaicism: Tracing subtle mutations in our brains

brain genetic mosaicism
(Erik Jacobsen, Threestory Studio. Used with permission.)
DNA sequences were once thought to be the same in every cell, but the story is now known to be more complicated than that. The brain is a case in point: Mutations can arise at different times in brain development and affect only a percentage of neurons, forming a mosaic pattern.

Now, thanks to new technology described last week in Neuron, these subtle “somatic” brain mutations can be mapped spatially across the brain and even have their ancestry traced.

Like my family, who lived in Eastern Europe, migrated to lower Manhattan and branched off to Boston, California and elsewhere, brain mutations can be followed from the original mutant cells as they divide and migrate to their various brain destinations, carrying their altered DNA with them.

“Some mutations may occur on one side of the brain and not the other,” says Christopher Walsh, MD, PhD, chief of Genetics and Genomics at Boston Children’s Hospital and co-senior author on the paper. “Some may be ‘clumped,’ affecting just one gyrus [fold] of the brain, disrupting just a little part of the cortex at a time.”

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3D printing helps doctors plan a toddler’s craniofacial surgery

Plastic surgeon John Meara, MD, and neurosurgeon Mark Proctor, MD, in the Craniofacial Anomalies Program at Boston Children’s Hospital are early adopters of 3D printing technology. They put it to good use in caring for Violet, a buoyant toddler who was diagnosed before birth with a rare, complicated skull and facial defect. Using CT images, and with the help of the hospital’s Simulator Program, they were able to build a series of plastic 3D models of Violet’s skull and rehearse her surgery—months before Violet arrived from Oregon.

“I actually feel like I know her, because I’ve seen that model change and grow over the last several months,” said Meara just before the surgery. “We can see and feel the trajectory of where we will have to make certain cuts, and that’s never been possible before.”

Read more on 3D printing in medicine in the Boston Globe. Follow Violet’s journey in this four-part series, and in The New York Times.

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Seizure-detecting wristband could prevent sudden death from epilepsy

“My biggest fear is that if I am not there to help him, when I wake him up he will be dead from seizures.”

That mother’s fear has a sound basis. The risk for sudden death from epilepsy, or SUDEP, is as high as 1 in 100 in the sickest children with epilepsy, says Tobias Loddenkemper, MD, of the Epilepsy Center at Boston Children’s Hospital. Many of those seizures occur in sleep.

Loddenkemper has been testing a novel wristband that uses motion and sweat sensors to detect the onset of a seizure—upon which the device would sound an alert. So far, the device has performed well on tests at Boston Children’s, picking up more than 90 percent of generalized tonic-clonic (grand mal) seizures, says Loddenkemper. But more work is needed to reduce false alarms (often generated when children are playing video games) and enable to device to spot more subtle seizures that are less convulsive in nature.

“This work is triggered by some very personal experiences of parents calling my office telling me their child died in sleep from seizures,” says Loddenkemper. “I dread these calls. We want to prevent those calls.”

The device manufacturer has created a fundraising site to help further the wristband’s development.

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