At the interface between a growing fetus and the uterine wall of a pregnant woman, the placenta is a complex organ that allows nutrient uptake, waste elimination and gas exchange via the mother’s blood supply. But in some common and potentially serious pregnancy-related disorders, the exchange mechanisms and placental development go awry, leading to pre-eclampsia and intrauterine growth restriction, for example.
For Dr. Sascha Drewlo, a post-doctoral researcher in the lab of Dr. John Kingdom (Maternal Fetal-Medicine Specialist in the Department of Obstetrics and Gynaecology at Mount Sinai Hospital and a scientist at the Lunenfeld), studying early placental development is like a window into observing, and intervening, in these pregnancy-related diseases, which are a major cause for fetal and maternal morbidity worldwide.
Dr. Drewlo studied molecular biology and genetics in Germany, and while completing his PhD work at the University of Cologne and Medical School of Aachen, met Dr. Kingdom through his mentor. “In the early stages of my PhD I was always fascinated about how John explained the clinical relevance of our work. He is an inspiring and extraordinary mentor,” says Dr. Drewlo.
“John’s clinical work and my molecular experience created a perfect match for translational research. I am extremely grateful to work in this lab with my colleagues and friends.”
Since joining the Institute in 2007, he has focused his studies on the role of a protein called GCM1 in human placentation.
“We have shown that its presence is crucial for normal placental development. GCM1 regulates the growth of the fetal maternal interface as well as the maintenance of the human trophoblast stem cell population,” says Dr. Drewlo. Furthermore, he notes that levels of GCM1 are reduced in pre-eclampsia. Since there is no human in vitro model for pre-eclampsia and mice don’t develop the disease, Dr. Drewlo and others in the Kingdom lab have used gene silencing strategies to recapitulate many key aspects of pre-eclampsia ex vivo, providing other researchers the opportunity to use this model as a tool to investigate the syndrome.
Last year, researchers in the Kingdom lab authored four key papers in important medical journals—no small feat for a team of only four trainees mentoring under Dr. Kingdom.
“We’re one of the smallest labs at the Lunenfeld but our passion has translated into a wealth of publications, and has brought us incredibly fruitful collaborations with other teams at the institute working in the areas of women’s and infants’ health,” says Dr. Drewlo.
Recently, the Kingdom lab has been investigating molecular intervention strategies with known drugs and the effects on placental physiology and placental dysfunction in disease. In one such study last May, Drs. Kingdom and Drewlo discovered a new mechanism for the blood thinning drug heparin to prevent severe high blood pressure in pregnancy, and the ensuing, potentially fatal effects on a developing baby. The study was published in the leading medical journal Obstetrics and Gynecology.
In pregnancy, heparin is often prescribed in lower doses, in an attempt to prevent recurrent miscarriages and other pregnancy-related complications that are thought to be due to placental blood clots, or thrombosis. However, the exact mechanism by which the drug exerts its effects in pregnant women with pre-eclampsia was unknown.
“Our new findings have considerable significance for the use of heparin to prevent serious pregnancy-related complications,” says Dr. Drewlo. “Our data present a novel and exciting picture of exactly how heparin exerts its beneficial effects on the placenta to prevent the development of pre-eclampsia.”
In a woman with pre-eclampsia, parts of the baby’s placenta exposed to the maternal blood (called placental villi) release natural inhibitory factors. These factors are important for placental growth, but interfere with the mother’s blood vessel function if levels are found to be abnormal.
Surprisingly, the researchers found that placental villi from healthy early pregnancies have the same inhibitory effect on blood vessels, but it fades to normal as healthy pregnancy proceeds. Heparin completely reversed this effect in early pregnancy, and was able to restart a limited degree of new blood vessel growth (angiogenesis) in some of the pre-eclamptic pregnancies, thus reducing the risk of high blood pressure in vitro (maternal endothelial dysfunction).
“We anticipate that a clearer understanding of how heparin works in pregnancy opens new avenues for more effective, safer use of the drug in other areas of obstetrics,” says Dr. Drewlo.
In recognition of Dr. Drewlo’s innovative and impactful research efforts, he was recently awarded a Travel Award from the Lunenfeld’s Research Training Centre, the 2012 JW Knox Ritchie Research Awards for best abstract/presentation Knox Richie, and the lab’s research was awarded the Pfizer President's Presenter's Award at a recent meeting of the Society of Gynecologic Investigation.
Dr. Drewlo is currently interviewing at several universities for positions as a professor, and plans to continue his work on the molecular mechanisms underlying pregnancy related disorders and human development.
“Sascha has worked with tremendous passion and energy at the Lunenfeld,” says Dr. Kingdom. “In addition to his own well-deserved achievements, Sascha has always been generous of his time to more junior trainees and has worked hard to ensure the success of our Biobank. In short, a superb post-doc—well done!”
Pre-eclampsia occurs in about seven to 10 per cent of pregnancies and may develop from 20 weeks’ gestation, often leading to pre-term delivery or poor fetal growth. Apart from Caesarean section or induction of labour, there is no known cure and previous drug approaches have been unsuccessful. It is the most common and dangerous pregnancy-related complication that affects both mother and unborn child.