Biology Becomes Electric
Preventing Premature Labor
Biomedical scientist Kathleen Morgan inspects a protein gel containing collections of proteins called “adhesion plaques,” which link actin to potentially druggable therapeutic targets at the cell surface.
Like De Luca, biomedical scientist Kathleen Morgan is deciphering electrical activity in the muscle, but in an entirely different sphere: the uterus. Morgan's research aims to better understand how uterine electrical signals trigger premature contractions, and ultimately to facilitate the development of a drug that could delay them. While medical science has improved its track record for keeping premature infants alive over the past three decades, there remains no truly effective way to halt preterm labor and the potentially serious lifelong disabilities that can go with it.
The growing fetus builds up stress on the uterus, which increases electrical activity in uterine smooth muscle cells—activity that tends to cause contractions. In humans, these electrical signals are uncoupled from any contractile activity until days before delivery. The mechanism that allows electrical activity to be uncoupled from mechanical activity for the normal duration of pregnancy has eluded scientists for many years, but Morgan now believes that she and her co-investigators have identified the molecules and processes responsible.
Morgan believes she and her co-investigators have identified the long-elusive molecules and processes that allow electrical activity to remain uncoupled from mechanical activity for the normal duration of pregnancy.
In collaboration with Yunping Li of Harvard University Medical School, a practicing obstetrical anesthesiologist at Beth Israel Deaconess Medical Center (BIDMC), and with the support of their research assistant Maya Reznichenko, Morgan has spent the last five years homing in on the primary molecules and interactions that trigger premature labor. By experimenting with rats, whose gestation period is only 21 to 23 days, the scientists identified two of the key molecules: extracellular regulated kinase (ERK) and caldesmon. Until labor, ERK causes caldesmon to prevent a third molecule, myosin—which, along with the protein actin, forms the contractile element of muscle—from causing a contraction. “All contraction pretty much comes down to myosin and actin interacting like a motor moving down train tracks,” says Morgan. “Caldesmon prevents the myosin from moving down the tracks laid by actin and causing a contraction.”
An immortalized cell line of the sort of smooth muscle cells that make up the wall of the uterus. Postdoctoral researcher Susanne Vetterkind, a member of Morgan's lab, used immunofluorescence to visualize actin (green), a myosin binding protein (red), and DNA in the nucleus (blue) of each cell.
In an NIH-funded study published in the August 2004 edition of the American Journal of Physiology, Morgan and her co-investigators gave the abortion pill RU486 to rats. As a result, ERK inhibited the action of caldesmon, thus leading to contractions and early labor. The researchers next gave the rats a combination of RU486 and another drug, U0126, that inhibits ERK activity. The animals did not go into labor. To learn whether inhibitors of ERK might be used in the treatment of preterm labor in humans, Li has obtained tissue samples from consenting BIDMC patients undergoing cesarean section.
One critical problem remains: ERK is not considered to be easily “druggable” because it resides deep inside the uterine muscle cell. “In signal transduction you have signals being transmitted to effectors through a cascade of molecules,” says Morgan. “We're going upstream to look at signals that are physically closer to the surface of the cell, which would be more accessible to therapeutics.” Eventually the researchers aim to collaborate with a drug company to tweak the chemistry of U0126 to better target the uterine ERK molecule.
For more information, see http://people.bu.edu/kmorgan/MorganLabHomepage.html.
