Charles Graham, Ph.D

Pregnancy and the problem of maternal inflammation

Estimated to affect as much as 3-8% of all pregnancies, pre-eclampsia (PE) can lead to serious health complications such as hemorrhaging, seizures, and kidney/heart failure.

Yet pre-eclampsia is only one of many complications of pregnancy that are often associated with an abnormal state of systemic inflammation in affected women; characterised by high levels of pro-inflammatory factors in the blood, such systemic inflammation can also lead to spontaneous pregnancy loss and fetal growth restriction.

“Babies who are born too small are referred to as growth restricted,” explains Dr. Charles Graham, Professor in the Department of Biomedical and Molecular Sciences at Queen’s University.  “These babies are at an increased risk of suffering from diabetes and heart disease in their adult lives.”

Promise of healthier pregnancies

New research out of Dr. Graham’s team at Queen’s University may lead to turning the tide in these unhealthy pregnancies and the millions of women and babies who suffer their consequences.

Working with lead author Tiziana Cotechini (PhD student, Biomedical and Molecular Sciences) and co-authors Maria Komisarenko, Arissa Sperou, Shannyn Macdonald-Goodfellow and Michael A. Adams, Dr. Graham’s recent investigations have shown that anti-inflammatory drugs could be beneficial in the treatment of abnormal maternal inflammation during pregnancy, helping to stave-off the associated diseases like pre-eclampsia and fetal growth restriction.

“In our rat model, we established a causal relationship between abnormal inflammation and the development of fetal growth restriction and a pre-eclampsia-like state,” explains Dr. Graham.  “Thus, if our findings can be extrapolated to the human condition, it might be possible to prevent and/or ameliorate pregnancy complications associated with abnormal inflammation by judiciously managing abnormal inflammation.”

Funded by the Canadian Institutes of Health Research and published in the Journal of Experimental Medicine, the promising research couldn’t have come soon enough – there are currently no effective treatments to prevent fetal growth restriction or pre-eclampsia as doctors do not fully understand the factors that cause these diseases.

Women who are unable to have babies because they keep on losing their pregnancies as a result of aberrant inflammation could potentially benefit by having their inflammation carefully managed. The same applies to women who suffer from pre-eclampsia and/or who have babies that are too small due to similar causes.

“Complications of pregnancy can have long-term health consequences to both the affected mothers and their babies”, explains Dr. Graham. “Babies who are too small at birth are at an increased risk of cardiovascular disease and diabetes later on in adult life; women who suffer pre-eclampsia are also at a higher risk of developing cardiovascular disease later on in life.”

Bringing people and ideas together

Dr. Graham joined queen’s University in 1994 after completing his doctoral studies at the University of Western Ontario and a post-doctoral fellowship at Sunnybrook Health Science Centre in Toronto.

“As a graduate student, I was interested in the biology of the human placenta,” admits Dr. Graham. “It’s fascinating. Like a malignant tumour, the human placenta is an invasive organ, as it needs to erode the wall of the uterus in order to gain access to maternal blood. However, too much invasion can lead to damage of the uterus whereas too little invasion may not allow for adequate fetal-maternal exchange. In our rats studies, abnormal maternal inflammation restricted the ability of placental cells to invade the uterus”

Other studies from Dr. Graham’s group have uncovered a novel mechanism by which the local tumour microenvironment, and in particular hypoxia, contributes to drug resistance, metastasis, and immune escape in cancer cells. Specifically, his research has shown that malignant adaptations to hypoxia are closely linked to nitric oxide signalling. This finding has led to the development of new modalities for the treatment of prostate cancer, which are currently under investigation in clinical trials.

While Dr. Graham’s studies in placentation and cancer progression may seem disparate, he explains that the placenta and malignant cancers share important similarities such as this ability to invade surrounding tissues. 

“Another similarity between the placenta and malignant tumours is that they both develop ways to avoid destruction by the immune system,” he explains. “Being of fetal origin, the placenta is considered to be a natural allograft, as it inherits genes from both the mother and the father.”

Similarly, Dr. Graham notes that cancers often express cell surface molecules that are recognised as foreign by the immune system and yet the placenta and advanced malignant cancers are not rejected by the immune system.  Some of the immune avoidance mechanisms may indeed be shared by the placenta and cancer.

“Because of this, it’s clear that our two research interests are complementary, and knowledge generated in one often informs the other,” he explains.

Dr. Graham feels that his greatest professional accomplishment is to have mentored some of the brightest trainees in Canada, some of whom have already become leaders in their field.

“I like being a positive influence on trainees,” he says. “I get a great deal of satisfaction in being able to share with them the excitement of a new discovery, of a manuscript accepted for publication, or of them receiving an award.”

“That’s one of the reasons why our group will continue investigating the role of inflammation in diseases of pregnancy and how anti-inflammatory drugs may be a beneficial treatment option,” he adds.  “To partake in their development as individuals and productive citizens is an amazing experience.”