Birth defects research

• The processes of development still hold many mysteries.
• We're working to prevent birth defects and find treatments.
• Sought: genetic and environmental causes of birth defects.

Detailed knowledge of how each of our organ systems develops is far from complete. Many March of Dimes grantees are conducting research on basic biological processes of development. Grantees continue to probe how specific genes guide the development of each organ, and how environmental factors may influence the process. Better understanding of normal and abnormal development provides a much-needed basis for developing new strategies to prevent or treat specific birth defects.

Some grantees are exploring a remarkable process that occurs before fertilization that is crucial for normal development. Developing egg and sperm cells undergo a specialized form of cell division called meiosis that reduces the number of chromosomes by half so that the embryo ends up with the correct number of chromosomes (23 pairs of chromosomes, or 46 in all).

Sometimes during meiosis, egg or sperm cells end up with too many or too few chromosomes. When fertilization occurs, errors in chromosome number lead to miscarriage, stillbirth or birth of a baby with chromosomal birth defects, such as Down syndrome. March of Dimes grantees are seeking to understand the cellular mechanisms that help assure that meiosis runs smoothly, in order to learn what can go wrong. Some grantees are seeking to identify genes that may help control proper pairing and separation of like chromosomes, while others are examining mechanisms cells use to help prevent these errors. For example, Andreas Hochwagen, MSc, PhD, is studying a signaling mechanism called the meiotic checkpoint that may halt meiosis when dividing cells contain errors, allowing the cell time to correct the errors. These grants may provide new insight into the underlying causes of chromosomal birth defects, which affect about 1 in 150 babies, a crucial step in learning to prevent them.

Many other grantees are studying genes that regulate the development of various organ systems, including certain 'master genes' that guide embryonic cells to the appropriate sites to form the heart, limbs, eyes, spinal column and brain. One of the most complicated organ systems to build is the brain. Many genes take part in this complex process that starts in the earliest days of pregnancy and continues after birth. Errors can occur at any step along the way, sometimes resulting in intellectual disabilities, seizures or even death.

March of Dimes grantees are studying all stages of brain development. Some examine the early stages when the brain cleaves into the right and left hemispheres. Others look at what happens after the basic architecture necessary for normal brain function is in place. For example, during the third to fifth month, billions of nerve cells migrate from their birthplace in the brain to the cerebral cortex, the thinking part of the brain. Serious abnormalities in this migration can lead to lissencephaly ("smooth brain"), a severe brain malformation in which the surface folds of the brain are missing. Affected children have severe mental retardation and usually do not survive. Orly Reiner, PhD, of Weizmann Institute of Science in Israel, is exploring the role of a gene in regulating this migration for insight into its role in causing lissencephaly as well as more subtle learning problems. Other grantees study how nerve cells form connections and communicate with each other, which could help explain how miswiring of the brain may contribute to intellectual disabilities and autism.