In a way, a deadly fly brought Dr. Wendy Kuohung to her latest line of research. But it didn’t happen overnight; it took thousands of years. In fact, for the vast majority of her life, she didn’t spend much time thinking of winged insects at all.
Dr. Kuohung, a Boston physician-scientist and 2025 March of Dimes Discovery Grant recipient whose research seeks to find medicines to treat a genetic variant-caused preeclampsia, has spent her career in women’s reproductive health.
As a fertility doctor, she helps women conceive. As an OB-GYN, she performs surgery on women whose pregnancies are at risk. As a professor, she teaches the next generation of doctors how to do the same. As a scientist, she uncovers the hidden secrets of the placenta. In many ways, she’s seen it all.
If you told her 15 years ago that her research into drugs to combat preeclampsia, a mysterious hypertensive disorder of pregnancy that disrupts healthy placental development, would stem from the blood-feeding African tsetse fly, she’d probably give you a look.
“I would have been skeptical,” said Dr. Kuohung, who is an Associate Professor of Obstetrics & Gynecology at Boston University Chobanian & Avedisian School of Medicine and the Director of the Division of Reproductive Endocrinology at Boston Medical Center. “Back then, it would have seemed far-fetched.”
That’s because the discovery that preeclampsia, the second leading cause of maternal death globally, has a genetic link that dates back to a fly in Sub-Saharan Africa, which is new.
It was only recently that scientists discovered preeclampsia could be caused by APOL1 gene variants that became widespread in people from Sub-Saharan Africa to protect against the Trypanosoma parasite carried by the tsetse fly. The common variants, of which there are two, G1 and G2, offered immunity against “sleeping sickness,” (African trypanosomiasis), the parasite-caused disease that disrupts sleep, causes seizures, and may result in death.
And though the variants saved lives, they had two unintended consequences. First, it was discovered about a decade ago that the variants increased risk for chronic kidney disease. Then, about five years ago, scientists reported the same variants also seemed to increase risk for preeclampsia. It was one of the first genetic links to preeclampsia described in populations with African ancestry, who suffer from the highest rates of preeclampsia complications. The news sent a bolt of energy through the preeclampsia research community.
“This was really exciting because it opened new opportunities for scientists to study this type of preeclampsia,” said Dr. Kuohung. “I was hooked—and that’s how this fly entered my life.”
Preeclampsia is one of the most dangerous pregnancy complications globally, and in the US, Black women face a 60% higher risk of this condition than white women. Though research is limited, it is believed that APOL1 variants likely account for about 12% of preeclampsia cases among this population, and because the variant can be traced back to Sub-Saharan Africa, the risk mainly applies to babies whose parents are descendants of that region.
Researchers know that this type of preeclampsia is partly a result of the babies’ genetic makeup. If one of the babies’ parents transmits an APOL1 variant to the baby, the baby will have a heightened preeclampsia risk. If both parents transmit a variant, the baby will have two variants, increasing risk even further. Still, two variants don’t guarantee manifestation of the disease. Scientists know there must be some additional ‘hit’, or triggering factor, to develop the disease—but they don’t know what. Though recent research has illuminated much about this type of preeclampsia, the field is ripe for breakthroughs.
It's with that understanding that Dr. Kuohung began pondering how she could contribute.
“I wanted to learn more about the development of this disease in placental cells and to discover new drugs to treat it at the same time,” she said.
There was one clear way to do that.
“To grow immortalized cell lines that express the variants,” Dr. Kuohung said.
So, she began. And last year, looking for more resources to continue the project, she applied for a March of Dimes Discovery Research Grant. In February, she received a $200,000 grant to carry on her work.
“This grant was absolutely critical to support the investigation,” she said. “And now, we’re making great headway.”
The first immortalized cell line was discovered in 1951, and growing immortalized cells has since become a common scientific practice. The cells are popular among researchers because they can be grown indefinitely in a laboratory and are not bound by the limited lifespan of a typical cell.
In the case of Dr. Kuohung’s research, she's growing three types of cells in her Boston University lab: placental cells expressing the normal copy of the APOL1 gene (G0), placental cells carrying the G1 variant, and placental cells carrying the G2 variant. By adding an antibiotic to the variant cells, she can turn gene expression on, allowing them to express the variant and behave like preeclamptic placental cells.
It's when the preeclamptic cells are ‘on’ that Dr. Kuohung can do her most anticipated work as part of the project: first, she can watch the development of the cells and make observations about the pathways they use to grow, proliferate, and interact. Second, and perhaps most exciting, she can test different therapeutic compounds on the cells to see which ones might make good candidates for medicines to treat this type of preeclampsia.
“We’re finally at the fun part,” Dr. Kuohung said. “We’re ready to introduce the cells to the different drug compounds and see their reactions.”
Getting here took time. The cells, invisible to the naked eye but appearing as tiny misshapen raindrops under a microscope, are meticulously cared for. Culture media, the nutrient-rich liquid in which they are submerged in small petri dishes, is replaced every several days. Antibiotics are added to the media to protect them from bacterial infections. And they spend most of their time in a warm incubator that promotes their comfortable growth.
All in preparation for the big event: the moment when Dr. Kuohung treats the cells with the antibiotic to turn them on ahead of running a special assay, or scientific test, that involves introducing the cells to the drug compounds and watching for reactions.
“Once we run the assay,” she said, “the cells should light up.”
The light signals an increased expression of an important protein that acts as a marker of stress, GRP78. And since placental cellular stress is a key characteristic of early preeclampsia, seeing how this protein reacts to compounds is one way to identify drug candidates.
“In this case, when we turn a cell on and run the assay, the appearance of light means the cell is stressed, which is the expected outcome for preeclamptic cells,” said Dr. Kuohung. “And when we treat the cells with drug compounds, we’re looking for that light to dim, meaning the medication is helping the cells by lessening stress.”
“And it’s those compounds that might be useful in fighting preeclampsia.”
The compound testing is expected to go quickly. Although Dr. Kuohung is starting initially with over 5,000 compounds to test, she doesn’t need to test each one individually. Her assay can test hundreds of compounds at once.
“We hope to have some promising drug candidates by next year,” she said. “And then we’ll plan validation studies to replicate the findings in different assay types.”
Since these cells are immortalized and don’t have an expiration date, Dr. Kuohung is expecting them to net limitless insights about the developmental pathway of this type of preeclampsia, the similarities between different types of preeclampsia, and the therapeutics that may stop the disease’s various manifestations in their tracks. The future is bright, she said.
“After decades of having no way to treat preeclampsia other than delivering the baby and placenta, I hope the tide is turning—and these immortalized cell lines might just be the reason why.”