New methods can find mutations that strike just 1 in 10 cells in a sample.
It’s become clear that our DNA is far from identical from cell to cell and that disease-causing mutations can happen in some of our cells and not others, arising at some point after we’re conceived
. These so-called somatic mutations—affecting just a percentage of cells—are subtle and easy to overlook, even with next-generation genomic sequencing. And they could be more important in neurologic and psychiatric disorders than we thought.
“There are two kinds of somatic mutations that get missed,” says Christopher Walsh, MD, PhD, chief of Genetics and Genomics at Boston Children’s Hospital. “One is mutations that are limited to specific tissues: If we do a blood test, but the mutation is only in the brain, we won’t find it. Other mutations may be in all tissues but in only a fraction of the cells—a mosaic pattern. These could be detectable through a blood test in the clinic but aren’t common enough to be easily detectable.”
That’s where deep sequencing comes in. Reporting last month in The New England Journal of Medicine, Walsh and postdoctoral fellow Saumya Jamuar, MD, used the technique in 158 patients with brain malformations of unknown genetic cause, some from Walsh’s clinic, who had symptoms such as seizures, intellectual disability and speech and language impairments. Full story »
Healing from nerve injuries gets slower as we age--here's why.
About six weeks ago, a glass shattered in my hand, severing the nerve in my pinky finger. The feeling in my fingertip still hasn’t returned, and now I know why: I’m too old.
Going back to World War II, it’s been speculated that recovery of peripheral nerve injuries—like those in limbs and extremities—is influenced by age. And studies indicate that peripheral neuropathy is common in people over 65 and often unexplained.
“When you’re very young, the system is very plastic and able to regenerate,” Michio Painter told me recently. He is a graduate student in the laboratory of Clifford Woolf, PhD, director of the F.M. Kirby Neurobiology Center at Boston Children’s Hospital. “After that, there’s a gradual decline. By the age of 30, much of this plasticity is gone.”
Traditionally, this decline has been thought to reflect age-related differences in neurons’ ability to regrow, but when Painter studied neurons in a dish, he couldn’t confirm this. Full story »
Credit: Samantha Morris, PhD, Boston Children's Hospital
If you’ve lost your way on the Boston subway, you need only consult a map to find the best route to your destination. Now stem cell engineers have a similar map to guide the making of cells and tissues for disease modeling, drug testing and regenerative medicine. It’s a computer algorithm known as CellNet.
As in this map on the cover of Cell, a cell has many possible destinations or “fates,” and can arrive at them through three main stem cell engineering methods:
• reprogramming (dialing a specialized cell, such as a skin cell, back to a stem-like state with full tissue-making potential)
• differentiation (pushing a stem cell to become a particular cell type, such as a blood cell)
• direct conversion (changing one kind of specialized cell to another kind)
Freely available on the Internet, CellNet provides clues to which methods of cellular engineering are most effective—and acts as a much-needed quality control tool. Full story »
Emmie Mendes was lucky enough to be diagnosed before age 3, but many families face a much longer journey.
At first, Corrie and Adam Mendes thought their daughter Emmie had an inner ear problem. She was late with several early milestones, including walking, and when she did walk, she often lost her balance. The family pediatrician sent them to a neurologist, who ordered a brain MRI and diagnosed her with pachygyria, a rare condition in which the brain is smoother than normal, lacking its usual number of folds.
Additionally, Emmie’s ventricles, the fluid-filled cushions around the brain, looked enlarged, so the neurologist recommended brain surgery to install a shunt to drain off fluid. He advised Corrie and Adam that Emmie’s life expectancy would be greatly reduced.
As Corrie recounts on her blog, Emmie’s Story, she went online and came across the research laboratory of Christopher Walsh, MD, PhD, at Boston Children’s Hospital. The lab does research on brain malformations and has an affiliated Brain Development and Genetics Clinic that can provide medical care.
After Walsh’s team reviewed Emmie’s MRI scan, genetic counselor Brenda Barry invited the family up from Florida. Full story »
At TEDx Longwood this spring, Leonard Zon, MD, founder and director of the Stem Cell Program at Boston Children’s Hospital, took the stage. In his enthusiastic yet humble style, he took the audience on a journey that included time-lapse video of zebrafish embryos developing, a riff by Jay Leno and a comparison of stem cell “engraftment” to a college kid coming home after finals: “You sleep for three days, and on day 4, you wake up and you’re in your own bed.” Three takeaways:
1) Stem cells made from our own skin cells can help find new therapeutics. With the right handling, they themselves can be therapeutics, producing healthy muscle, insulin-secreting cells, pretty much anything we need. (So far, this has just been done in mice.)
2) Zebrafish, especially when they’re see-through, can teach us how stem cells work and can be used for mass screening of potential drugs. The Zon Lab boasts 300,000 of these aquarium fish, and can mount robust “clinical trials” with 100 fish per group.
3) Drugs discovered via zebrafish are in human clinical trials right now: A drug to enhance cord blood transplants for leukemia or lymphoma, and an anti-melanoma drug originally used to treat arthritis.
Zon, who co-founded the biopharm company Fate Therapeutics, will be part of a judging panel of clinicians and venture capitalists for the Innovation Tank at Boston Children’s Global Pediatric Innovation Summit + Awards (Oct. 30-31). Don’t miss it!
A restored, clear cornea grown from ABCB5-positive limbal stem cells. (Image courtesy of the researchers)
Severe burns, chemical injury and certain diseases can cause blindness by clouding the eyes’ corneas and killing off a precious population of stem cells that help maintain them. In the past, doctors have tried to regrow corneal tissue by transplanting cells from limbal tissue—found at the border between the cornea and the white of the eye. But they didn’t know whether the tissue contained enough of the active ingredient: limbal stem cells.
How cancer research led to a regenerative treatment for blindness.
Results have therefore been mixed. “Limbal stem cells are very rare, and successful transplants are dependent on these rare cells,” says Bruce Ksander, PhD, of the Massachusetts Eye and Ear/Schepens Eye Research Institute. “If you have a limbal stem cell deficiency and receive a transplant that does not contain stem cells, the cornea will become opaque again.”
Limbal stem cells have been sought for over a decade. That’s where a “tracer” molecule called ABCB5—first studied in the context of cancer—comes in. Full story »
Prenatal cell therapy could avoid the need for invasive surgery to repair myelomeningocele.
The neural tube, which becomes the spinal cord and brain, is supposed to close during the first month of prenatal development. In children with spina bifida
, it doesn’t close completely, leaving the nerves of the spinal cord exposed and subject to damage. The most common and serious form of spina bifida, myelomeningocele, sets a child up for lifelong disability, causing complications such as hydrocephalus, leg paralysis, and loss of bladder and bowel control.
New research from Boston Children’s Hospital, though still in animal models, suggests that standard amniocentesis, followed by one or more injections of cells into the womb, could be enough to at least partially repair spina bifida prenatally.
Currently, the standard procedure is to operate on infants soon after delivery. Full story »
My daughter just surprised me by signing up for fifth grade band starting this fall. To my further delight, some new research—using both cognitive testing and brain imaging—suggests that as she practices her clarinet, she also may be honing her executive functions.
Like a CEO who’s on top of her game, executive functions—separate from IQ—are those high-level brain functions that enable us to quickly process and retain information, curb impulsive behaviors, plan, make good choices, solve problems and adjust to changing cognitive demands. While it’s already clear that musical training relates to cognitive abilities, few previous studies have looked at its effects on executive functions specifically.
The study, appearing this week in PLOS ONE, compared children with and without regular musical training, as well as adults. To the researchers’ knowledge, it’s the first such study to use functional MRI (fMRI) of brain areas associated with executive function and to adjust for socioeconomic factors. Full story »
One of my very favorite images in science, Dr. Wilder Penfield’s classic motor homunculus, shows how much brain real estate is devoted to controlling movement of different parts of the body. Notice the huge hands and the tiny feet. As the World Cup gets underway, soccer fan Jeffrey Holt, PhD, also a Boston Children’s Hospital neuroscientist, writes that soccer is more than just a great sport, it’s “a triumphant display of the incredible plasticity of the human brain… because the soccer player is limited by one simple rule: no hands!”
Though no one’s actually taken a look, Holt imagines that the brains of great soccer players like Cristiano Ronaldo, Lionel Messi or Neymar would have much expanded neural representation of the feet. Read more in his post on WBUR-Boston’s Cognoscenti blog.