A 90 Year Old Mystery Solved with Molecular Biology

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Mary Loeken, Ph.D., Investigator in the Section on Islet Cell and Regenerative Biology at Joslin and an Associate Professor of Medicine at Harvard Medical School.

Mary Loeken, Ph.D., Investigator in the Section on Islet Cell and Regenerative Biology at Joslin and an Associate Professor of Medicine at Harvard Medical School.

When you have diabetes, pregnancy can seem kind of scary. From overdramatized stories in the movies to real life risks like diabetic retinopathy, congenital malformations, and delivery complications, including  hypoglycemia in the infant, there’s a lot more to worry about than in your average pregnancy. But researchers at Joslin are trying to figure out why and how these complications happen. Because of their work, we’re getting a view of diabetic pregnancies in finer and finer detail—which may just lead to possible therapies or cures.
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This October, Mary Loeken, Ph.D., investigator in the Section on Islet Cell and Regenerative Biology at Joslin and an associate professor of medicine at Harvard Medical School, published a study detailing a molecular pathway responsible for neural tube defects in diabetic pregnancies.

Even before the Joslin clinic opened in 1898, physicians had been concerned that women with diabetes (both type 1 and type 2) had far more difficulties undergoing successful pregnancies. Even with modern methods to treat diabetes, women with diabetes have a higher risk of having a child with a variety of birth defects. Neural tube defects are one of the most serious complications. A neural tube is the body’s first step in assembling the spinal cord and brain. This happens very early, within the first two to four weeks of gestation, usually about the time a woman first realizes she’s pregnant.
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When the body folds new cells into a neural tube it starts fusing at the center, zips together towards the base of the spine and the top of the head, and finishes by sealing each end—sort of like a long, skinny calzone folding over itself. If at any point along the spinal cord of the tube does not close, the baby develops spina bifida, which can lead to motor impairment and other disabilities. If the top end of the tube stays open the baby develops a much more serious malformation called anencephaly where the fetus is missing a significant portion of its brain. Most babies with anencephaly do not survive more than a few hours after birth.

Even after the discovery of insulin 1921, many women didn’t survive their pregnancies long enough to see these malformations. Dr. Priscilla White, who joined the clinic in 1924, wanted to help these women and their babies. She began an intensive program to help women with diabetes live through their pregnancies.

“During the course of her career, Dr. White made it possible for women with diabetes to have children, yet there were still a lot of unanswered questions,” says Dr. Loeken.
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Even with relatively good control of diabetes, Dr. White noted that the incidence of malformations was still significantly higher than in non-diabetic populations. “And that continues to be the case, although when diabetic women plan their pregnancies and control their blood sugar early in pregnancy, the rate of birth defects can be close to that in nondiabetic pregnancies.” says Dr. Loeken. “I’m so grateful for the work she did and that I’ve been able to carry it on at a basic science level.”

The causes of these malformations have remained murky. But more than eighty years after Dr. White started taking care of women’s pregnancies, Dr. Loeken has unearthed a critical piece of the puzzle—a molecule that halts a gene responsible for neural tube closure.

Using a diabetic mouse model, Dr. Loeken homed in on Pax3, a gene she’s been studying for over twenty years. Since the early 1990’s, scientists have known Pax3 tells the body to close the neural tube. Dr. Loeken just had to figure out why Pax3 went awry in diabetic pregnancies.

In previous research, she found that Pax3 is sensitive to high levels of glucose. When exposed to hyperglycemic events, Pax 3 doesn’t turn on when it is supposed to. Now, she has found exactly what prevents Pax3 from coming on.
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DNA Methyltransferase (Dnmt) is a family of enzymes responsible for altering the chemical building blocks of DNA, specifically adding a methyl group to cytosine (one of the four main bases in DNA’s “rungs”).

Imagine a wall of red bricks (the cytosine). Dnmt is like a painter moving along the red wall painting certain bricks blue (the auxiliary methyl group) where it thinks they should go. Dnmt doesn’t swap out the bricks, it just alters them a little. Sometimes the blue bricks are needed—they keep genes off when they shouldn’t be turned on. But if the blue bricks should turn red and they don’t, they completely mess up the pattern.

In a normal neural tube development, the Dnmt tapers off and stops adding those blue methyl groups. But if there is too much glucose, the Dnmt never slows down.

Dr. Loeken discovered that glucose over-stimulates DNA Methyltransferase, specifically the subtype Dnmt3b. The overactive enzyme keeps adding methyl groups to the cytosines near the Pax3 gene and prevents Pax3 from turning on so that it can close the neural tube.
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Although it would appear that the way to prevent neural tube defects would be to stop Dnmt3b, Dr. Loeken cautions against such radical treatment. “There are actually drugs that can be used to inhibit Dnmt; however we wouldn’t use a drug to interfere with this pathway because this is a tightly regulated process.” Dnmt isn’t an entirely bad enzyme; there are many genes critical for development that need to be switched on or off by Dnmt. Shutting it down entirely would create even more malformations.

“However,” says Dr. Loeken, “It does allow us to elucidate a biochemical pathway that we really didn’t understand before.” She explains that a safer method than chemically shutting off Dmnt would be to rigidly control a pregnant woman’s glycemic level.

“If the mother is under very tight glycemic control and avoids excursions above the level that will drive glucose into the cells, then all the events downstream, including the hypermethylation, will not occur,” she says.

A treatment that may come out of this research is better stem cell therapy. “We might be able to exploit these pathways to make more competent stem cells to repair the congenital malformations,” says Dr. Loeken. “And that’s not just limited to diabetes.”
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Neural tube defects happen in nondiabetic pregnancies as well, affecting about 1,500 births in the US every year and around 300,000 worldwide. Dr. Loeken’s research has already caught the attention of other scientists working on neural tube defects. Together, they may illuminate causes and treatments for all babies born with these malformations—and that may lead to a lot more happy, healthy babies.

 

2 Responses to A 90 Year Old Mystery Solved with Molecular Biology

  1. Jan says:

    Very cool research! It’s amazing how far we’ve come, too – used to be, diabetes was a very quick death sentence. Even within the last 30 years, it was still a very potent thing. Very promising to see so much more life – now if only we Americans would stop doing the very things that CAUSE it…..

    • Rosemarie Stone says:

      Jan, please be specific when choosing your words. “…we Americans do not cause or bring on Type I and although most cases of Type II are lifestyle driven, Type II onset can also be attributed to the ageing process in some people.

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