In the early stages of life, a group of cells in the developing embryo must come together to form the neural tube, which ultimately makes up the brain and the nervous system. If the cells move to the wrong place, fail to mature, or do not divide properly, the tube will not close and the embryo will suffer.
Problems with neural tube closure are the second most common human birth defect, causing spontaneous abortions, anencephaly (infants born without brains), and spina bifida, a paralyzing condition arising from spinal cord abnormalities.
Approximately seven years ago, Lee Niswander decided to tackle neural tube closure aberrations, banking on her 20 years of unraveling other mysteries of development. In her career, Niswander advanced fundamental knowledge about how limbs form, and created novel ways to use imaging and tissue culture to monitor developmental processes as they occur.
But she came to a point in her life when she wanted her research to have more clinical impact. "I am probably crazy to pursue neural tube closure because it is so complex," she said, yet hopes her past success will bode well for her current investigations.
How a fertilized egg divides and forms a living creature's structures, including its skeleton, brain, heart, and other organs, is one of the most complicated questions in biology. Indeed, it was the complexity of the field that drew Niswander to developmental biology. She enjoyed analyzing the steps required to shape an organism from its building blocks of DNA, proteins, and cells.
Her new goal is to identify genes that work to close the neural tube and find new ways to avert closure defects. Today, doctors recommend that women of childbearing age who are planning a family take folic acid, a vitamin that prevents closure defects. But no one knows how folic acid works and if other supplements might thwart the problem in those cases when the vitamin fails, Niswander said.
To discover the closure genes, Niswander selects for strains of mutant mice with neural tube closure defects, which she detects by observing embryos during early days of life, when the neural tube forms. She then searches for the gene responsible for the defect in each mutant. To date, Niswander has identified 12 genes; only one had been studied before.
With the gene in hand, she studies how abnormal or normal versions of it affect neural tube closure, including using her unique embryo culture and digital visualization techniques. She devised the test tube experiments because in an animal, scientists cannot observe developing cells moving, extending processes, or grouping together.
Niswander anticipates her work will contribute to new ways to prevent, diagnose, and treat closure defects. Her information may help identify genes in human families at risk for closure defects. Niswander also hopes to unearth drugs, besides folic acid, to prevent closure defects.
Past accomplishments in finding key molecules in limb development spur her expectations and "passion" for her new research. When Niswander was a postdoctoral fellow in the early 1990s at the University of California, San Francisco, she showed how one molecule, fibroblast growth factor-4 (FGF-4), made by a special group of cells called the apical ectodermal ridge (AER), could by itself promote undifferentiated cells of the early limb to grow and become arm or leg and digit bones.
Although developmental biologists from the 1940s through the 1980s had studied chick embryo limb development and knew AER cells were critical for limb development, the molecules participating in that process were unknown. Niswander discovered that among the thousands of proteins in AER cells, FGF-4 alone could stimulate adjacent immature cells to form the limb.
She worked with chick embryos because their limb development had been well-characterized and they provided an easy way to do experiments. A developing chick sits atop the yolk near the surface of the egg shell and scientists can remove cells microsurgically or add molecules without hurting embryonic development.
Over time, Niswander extended her limb research into mouse and bat models and found other proteins involved in the process. Bats—the only mammals that fly—are interesting because their digits are long and membranes between the digits remain to form the wing, unlike what happens in chicks and mice. Her work revealed how bone morphogenetic proteins (BMPs) and FGFs enable wing elongation and membrane construction.
Recently, she created another unique culture/imaging system to study how the early limb skeleton forms and to determine how BMPs affect this process. BMPs help aggregating, limb-developing cells form tighter associations so they can further mature. Without BMP, the clusters fall apart, resulting in skeletal defects. Today, she uses culture systems and animal models in both her limb and neural tube closure studies.
Niswander continues to be awed by what she studies. Unlike other aspects of biology—such as protein-protein interactions or a signal pathway contributing to a cell's behavior—developmental biology, she said, looks at the many factors that contribute to how we came to be what we are.