Before the discovery of insulin in 1922, children and adults who developed Type 1 diabetes usually died within a few months of the disease’s onset. That all changed when insulin became widely available, but women with diabetes still faced another challenge: significant odds that their offspring would be born with birth defects.
Even today, women diagnosed with diabetes (either Type 1 or Type 2) before they become pregnant have a greater risk of having a child with a severe birth defect than nondiabetic women.
In her laboratory at the Joslin Diabetes Center in Boston, Mary Loeken ’80, M.S., biological sciences, is studying mice to unlock the secrets of diabetic pregnancy. Eventually, she hopes to improve clinical practices so that the birth defect rate for children of diabetic and nondiabetic women is the same.
Loeken, who is also an associate professor of medicine at Harvard Medical School, began her research career at UMBC, studying under Professor Thomas F. Roth. She had previously earned an undergraduate degree in biology from Gonzaga University.
The UMBC of that era had a relatively young science faculty, with many excellent professors only a few years out of their own post-doctoral experiences. “[The faculty] were trained at really prestigious universities and laboratories,” Loeken says. “So I thought they would know what the expectations were for students to succeed in their careers, and would probably be energetic and looking for students to be involved.”
Loeken stayed in the area after graduating from UMBC, taking a Ph.D. in reproductive endocrinology at the University of Maryland’s School of Medicine, and then working as a post-doc at the National Institutes of Health in Bethesda in the then-new field of recombinant DNA technology.
The Joslin Diabetes Center, a teaching affiliate of Harvard Medical School, hired her to bring recombinant DNA technology to its program. Loeken became the co-head of the newly-formed Section on Molecular Biology, as well as the director of the center’s Molecular Biology Core Laboratory.
Loeken’s research focuses on why babies born to diabetic women are at much greater risk for birth defects – and how this risk might be lowered or prevented.
Approximately two percent of babies born to nondiabetic women develop congenital malformations. But that number rockets to three or four times higher for women who have diabetes – even if they have successfully controlled the disease and planned their pregnancies. The birth defect rate is even higher for diabetic women with unplanned pregnancies or unchecked diabetes.
Maternal diabetes can cause many kinds of birth defects, and many babies have more than one, especially congenital heart defects and neural tube defects. The neural tube defects include spina bifida (where part of the spinal cord is exposed) and anencephaly (where part of the brain is exposed).
Loeken studies the neural tube defects, partly because they also occur with high frequency in the mice she studies. She adds that these malformations are also easy to spot in mouse embryos.
The malformations have been tracked to a change in how a particular gene (Pax-3) expresses itself. Pax-3 is part of a family of genes involved in embryonic development. Contrary to what most scientists believed, Loeken and her colleagues discovered that Pax-3 regulates a tumor-suppressing protein called p53 which is either missing or mutated in almost all tumors.
“It was always thought that Pax-3 turned on genes needed for the formation of these structures” in developing embryos, Loeken observes. But she and her colleagues discovered was that if there is not enough Pax-3 present, then the embryo cells produce too much of the p53 protein.
While the p53 protein is actually doing its job in those cells to prevent cancer, the surfeit of the protein actually kills the cells needed to form structures such as the spinal cord properly. Thus, the overabundance of p53 is destructive at a crucial time in embryonic development.
In her research, Loeken has also discovered that when the embryo receives too much glucose – as occurs with diabetes – a delicate chemical balance that controls the expression of Pax-3 gene is upset.
Loeken says her investigations demonstrate why women with diabetes should endeavor to get their blood glucose levels as close to normal as possible before becoming pregnant.
“It’s still important for women to plan their pregnancies,” she says. “Most women with diabetes have healthy babies. The majority do. But because these birth defects are so devastating, as long as they are more common in diabetic pregnancies than in nondiabetic pregnancies, we will be working to understand how they occur and how to prevent them.”
— Joel N. Shurkin