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Basic science to save babies: Ananth Karumanchi and John Wallingford are bringing their expertise in molecular science to study the causes of premature birth and developmental problems.
Both findings shifted Rowitch's thinking. Boosting the brain's protective or repair mechanisms might be the best route for rescuing premature brains from permanent damage. How to help the brain help itself “is not a well-established area of research,” says Rowitch. “In some ways we are swimming in a deep ocean where you cannot see the bottom.” But that doesn't stop his group from pushing toward shore.
Although these key insights came from research models, Rowitch believes it is absolutely necessary to chart what goes wrong in the brains of premature infants. So when he became an HHMI investigator in 2008, he spent the first year wading through the paperwork, red tape, and delicate negotiations to set up the first-of-its-kind pediatric brain tissue bank.
One-third of babies born with severe brain injury do not survive, Rowitch says, and this bank represents those tragedies. But many families, he notes, take comfort in donating so that other babies might be saved in the future. Surveying brain tissue of premature babies is the only way to find out if the same cell problems and faulty repair mechanisms that Rowitch sees in his mouse models are present in the human brain. “It's so important to do this. We can learn even when things don't work out well.”
On a converted army base east of Denver, Lee Niswander's sparkling new University of Colorado laboratory building faces the sunny downtown skyline and its mountain backdrop. But the HHMI investigator rarely looks up from her microscope. She's usually too busy watching the neural tube—the structure that will become the brain and spinal cord—develop in real time in mouse embryos.
“No one has ever watched this process in a mammal,” she says. “We're seeing things that nobody has ever seen before.” Niswander's penchant for solving three-dimensional puzzles emerges when she talks about the “beautiful complexity” of neural tube closure.
In all vertebrate embryos, the neural tube starts out as a flat plate of cells. That plate must buckle inward, creating a furrow and two opposing neural folds. The folds come together and fuse to form the hollow tube that will become the central nervous system. These tissue movements are driven by complicated cell shifting and shuffling, which results in chunky parts becoming slimmer, bringing sections together at spots, and finally zipping closed down the length of the embryo's back.
In humans, the neural tube normally forms and closes by the fourth week after conception, before most women even know they are pregnant. It is one reason women are encouraged to eat well and take vitamins such as folic acid (which helps to ensure the neural tube closes correctly) long before they become pregnant. Failure of the tube to close properly causes a condition known as spina bifida, Latin for split spine—which exposes the spinal cord to the fluid in the womb. The resulting permanent neurological damage ranges from mild symptoms to partial paralysis. After heart defects, neural tube defects (NTDs) are the second most common type of serious birth defect.
“Because of the complexity, there are so many places where it can go wrong,” Niswander says. She explains that it's not just the cell movements that have to come off correctly, but all of the underlying genetic programming, biochemical signaling, and incoming environmental influences that together conduct this choreography. “Based on how many genes we already know are required for neural tube closure in mice, I would not be surprised if there were 800-1,000 genes that, if disturbed, might lead to a defect.”
So far, Niswander and her collaborators are actively working on about 30 genes in mice that lead to NTDs. Using a powerful microscope, her lab members observe cellular changes in the developing neural tubes of mouse embryos. In normal mice, they've seen that some cells at the edges of the opposing neural folds put out dynamic membrane extensions to communicate or firm up contacts across the gap. Although the data are very preliminary, Niswander says, at least some of the genetic mutations change this behavior of putting out feelers.
The closing of the neural tube, shown here in developing salamanders, is a vital step in embryo development.
Credit: John Wallingford
Niswander has begun to give the mutant mice folic acid supplements to study how the vitamin acts to prevent some NTDs. “Folic acid is touted as preventing up to 70 percent of NTDs in women. I want to know, how is it doing that?” she says. “It's totally daunting to think you could try to tackle NTDs,” she continues. “But as a developmental biologist, I think I can bring my expertise to make an impact on a very real problem in human biology.”
Like Niswander, HHMI early career scientist John Wallingford loves to watch development unfold. He also spends countless hours at the microscope, making videos of frog neural tubes as they curl and seal up.
The advantage of working with frogs? “Any kid who has gone out and caught tadpoles in a pond can tell you,” he says. Frogs develop outside the womb in open, clear water, which makes it a cinch for Wallingford's group to watch the whole process at the cellular, and even subcellular, level. They can also easily manipulate frog genes to find those critical to neural tube closure by microinjecting modifiers directly into embryos. This procedure lets Wallingford, at the University of Texas at Austin, screen hundreds of embryos at a time.
Photos: Karumanchi: Kaye Evans-Lutterodt / PR Newswire ©HHMI; Wallingford: Sasha Haagensen