Stories about: Science

Optic nerve regeneration: One approach doesn’t fit all

alpha retinal ganglion cells optic nerve regeneration
Alpha-type retinal ganglion cells (RGCs) in part of an intact mouse retina. The cell axons lead to the optic nerve head (top right) and then exit into the optic nerve. The alpha RGCs are killed by the transcription factor SOX11 despite its pro-regenerative effect on other types of RGCs. (Fengfeng Bei)

Getting a damaged optic nerve to regenerate is vital to restoring vision in people blinded through nerve trauma or disease. A variety of growth-promoting factors have been shown to help the optic nerve’s retinal ganglion cells regenerate their axons, but we are still far from restoring vision. A new study published yesterday in Neuron underscores the complexity of the problem.

A research team led by Fengfeng Bei, PhD, of Brigham and Women’s Hospital, Zhigang He, PhD, and Michael Norsworthy, PhD, of Boston Children’s Hospital, and Giovanni Coppola, MD, of UCLA conducted a screen for transcription factors that regulate the early differentiation of RGCs, when axon growth is initiated. While one factor, SOX11, appeared to be critical in helping certain kinds of RGCs regenerate their axons, it simultaneously killed another type — alpha-RGCS (above)— when tested in a mouse model.

At least 30 types of retinal ganglion cell message the brain via the optic nerve. “The goal will be to regenerate as many subtypes of neurons as possible,” says Bei. “Our results here suggest that different subtypes of neurons may respond differently to the same factors.”

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A new, much needed target for treating Candida albicans

Candida albicans

Fungal diseases commonly bring to mind the words “dangerous” or “difficult to cure.” Now, scientists might just be a step closer to treating diseases caused by one common, problematic fungus, Candida albicans, by targeting a key player unique to fungi in an important growth pathway.

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Why is one twin sometimes smaller than the other? The answer may lie in the placenta

placental oxygen transport may help determine fetal size

When a baby is born small, it’s often chalked up to genetics or to maternal risk factors like poor nutrition or smoking. A study of twin pregnancies, published today in Scientific Reports, finds another factor that can be measured prentally: slower transport of oxygen from mother to baby across the placenta.

The study, part of the NIH-funded Human Placenta Project, is the first to make a direct connection between placental oxygen transport and birth outcomes. It relies on a new, noninvasive technique called Blood-Oxygenation-Level-Dependent (BOLD) MRI. Developed by P. Ellen Grant, MD, director of the Fetal-Neonatal Neuroimaging and Developmental Science Center at Boston Children’s Hospital and Elfar Adalsteinsson, PhD at MIT, it maps oxygen delivery across the placenta in real time.

“Until now, we had no way to look at regional placental function in vivo,” says Grant.

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A surprising new link between inflammation and mental illness — and a potential drug to protect the brain

A synapse being attacked by microglia, which causes neuropsychiatric symptoms in lupus
In the brain, a synapse (red – see diagonal “spine” across center of photo) is seen being wrapped around and attacked by immune cells called microglia (green), leading to synapse loss. Credit: Carroll lab / Boston Children’s Hospital

Up to 75 percent of patients with systemic lupus erythematosus — an incurable autoimmune disease commonly known as “lupus” —  experience neuropsychiatric symptoms.  But so far, our understanding of the mechanisms underlying lupus’ effects on the brain has remained murky.

“In general, lupus patients commonly have a broad range of neuropsychiatric symptoms, including anxiety, depression, headaches, seizures, even psychosis,” says Allison Bialas, PhD, a research fellow working in the lab of Michael Carroll, PhD, of Boston Children’s Hospital. “But their cause has not been clear — for a long time it wasn’t even appreciated that these were symptoms of the disease.”

Collectively, lupus’ neuropsychatric symptoms are known as central nervous system (CNS) lupus. Their cause has been unclear until now.

Perhaps, Bialas thought, changes in the immune systems of lupus patients were directly causing these symptoms from a pathological standpoint. Working with Carroll and other members of his lab, Bialas started out with a simple question, and soon, made a surprising finding – one that points to a potential new drug for protecting the brain from the neuropsychiatric effects of lupus and other diseases. The team has published its findings in Nature.

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Helping tissue grafts build a blood supply: Less is more

blood vessels in vivo

For a tissue graft to survive in the body — whether it’s a surgical graft or bioengineered tissue — it needs to be nourished by blood vessels, and these vessels must connect with the recipient’s circulation. While scientists know how to generate blood vessels for engineered tissue, efforts to get them to connect with the recipient’s vessels have mostly failed.

“Surgeons will tell you that when putting tissue in a new location in the body, the small blood vessels don’t connect at the new site,” says Juan Melero-Martin, PhD, a researcher in Cardiac Surgery in Boston Children’s Hospital. “If you want to engineer a tissue replacement, you’d better understand how the vessels get connected, because if the vessels go, the graft goes.”

Melero-Martin and colleagues have uncovered several strategies to help these connections form, as they describe online today in Nature Biomedical Engineering. The strategies could help improve the success of such procedures as heart patching, bone grafting, fat transplants and islet transplantation.

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Flipping the switch on tumor growth

Pictures of angiogenic tumor cells
Time-lapse imaging can reveal tell-tale changes in cellular behaviors associated with tumor growth.

Without a blood supply, a tumor can remain dormant and harmless. But new blood vessel growth from an existing vessel, a process called angiogenesis, is a hallmark of both benign and malignant tumors. During angiogenesis, blood vessels invade tumors and activate them, fueling their growth.

Now, Marsha A. Moses, PhD, who directs the Vascular Biology Program at Boston Children’s Hospital, and members of her laboratory have revealed that a specialized imaging system can detect changes in cell behaviors. These changes predict when tumors are leaving a state of dormancy and becoming more likely to grow.

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Rare disease therapies: Three strategies to bridge the gap between research and industry

Rare disease research: DNA helix pictured here
Genetic mutations underpin many rare diseases.

Right now, there are about 7,000 rare diseases affecting 10 percent of Americans. Only five percent of these diseases have any FDA-approved treatment options.

Panelists:
David Williams, MD: President, Dana-Farber/Boston Children’s Cancer and Blood Disorders Center; Senior VP, Chief Scientific Officer and Chief of Hematology/Oncology, Boston Children’s
Wayne Lencer, MD: Chief of Gastroenterology, Hematology and Nutrition, Boston Children’s
Phil Reilly, MD, JD: Venture Partner at Third Rock Ventures
Alvin Shih, MD, MBA: Chief Executive Officer at Enzyvant

Even at a place like Boston Children’s Hospital, where doctors regularly see children with rare diseases from all over the world, there are big challenges when it comes to drug discovery and treatment.

“Roughly 70 percent of drugs to treat children are used off-label,” says David Williams, Boston Children’s chief scientific officer. “That’s because these drugs were initially developed for adults and have not been tested formally in children.”

In order to cure rare diseases in children and adults, scientists must bridge the gap between research and industry. On May 25, Boston Children’s Technology and Innovation Development Office (TIDO) and MassBio held a candid panel discussion about what it will take to advance the development of rare disease therapies. Here are three of the biggest takeaways

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Two resilient dogs point to new targets for Duchenne muscular dystrophy

Duchenne muscular dystrophy protective genes
Suflair, at right, is alive and well at 11 years despite having the DMD mutation (courtesy Natássia Vieira)

Two golden retrievers that had the genetic mutation for Duchenne muscular dystrophy (DMD), yet remained healthy, have offered up yet another lead for treating this muscle-wasting disorder.

For several years, Natássia Vieira, PhD, of the University of São Paolo, also a fellow in the Boston Children’s Hospital lab of Louis Kunkel, PhD, has been studying a Brazilian colony of golden retrievers. All have the classic DMD mutation and, as expected, most of these dogs are very weak and typically die by 2 years of age. That’s analogous to children with DMD, who typically lose the ability to walk by adolescence and die from cardiorespiratory failure by young adulthood.

But two dogs appeared unaffected. Both ran around normally. The elder dog, Ringo, lived a full lifespan, and his son Suflair is still alive and well at age 11.

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One family, one researcher: How Mikey’s journey is fueling an attack on DIPG

Picture of Mikey on 11th birthday, shortly after his DIPG diagnosis
Mikey and his family at his 11th birthday party, just one week after he was diagnosed with DIPG, a devastating tumor in his brain stem. Since Mikey’s passing in 2008, his family has been committed to supporting DIPG research.

“It’s a brutal disease; there’s just no other way to describe DIPG,” says Steve Czech. “And what’s crazy is that there aren’t many treatment options because it’s such a rare, orphan disease.”

Czech’s son, Mikey, was diagnosed with a diffuse intrinsic pontine glioma (DIPG) on Jan. 6, 2008. It was Mikey’s 11th birthday. The fast growing and difficult-to-treat brainstem tumors are diagnosed in approximately 300 children in the U.S. each year.

Sadly, the virtually incurable disease comes with a poor prognosis for most children. The location of DIPG tumors in the brainstem — which controls many of the body’s involuntary functions, such as breathing — has posed a huge challenge to successful treatment thus far.

“Typically, they give kids about nine months,” says Czech. “Our lives changed forever the day that Mikey was diagnosed.”

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Medical milestone: Making blood stem cells in the lab

blood stem cells
The gradation of pink-to-blue cells illustrates the transition from hemogenic endothelial cells to blood progenitor cells during normal embryonic blood development. Daley, Sugimura and colleagues recreated this process in the lab, then added genetic factors to produce a mix of blood stem and progenitor cells. (O’Reilly Science Art)

Pluripotent stem cells can make virtually every cell type in the body.  But until now, one type has remained elusive: blood stem cells, the source of our entire complement of blood cells.

Since human embryonic stem cells (ES cells) were isolated in 1998, scientists have tried to get them to make blood stem cells. In 2007, the first induced pluripotent stem (iPS) cells were made from human skin cells, and have since been used to generate multiple cell types, such as neurons and heart cells.

But no one has been able to make blood stem cells. A few have have been isolated, but they’re rare and can’t be made in enough numbers to be useful.

Now, the lab of George Daley, MD, PhD, part of Boston Children’s Stem Cell Research program as finally hit upon a way to create blood stem cells in quantity, reported today in Nature.

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