Learning the Secrets of Mega-Cells

BY ADRIANA V. DIFRANCO

What do fungi in the forest and human placentas have in common?

It sounds like a riddle, but it’s actually a fascinating biological conundrum. Fungi and placentas have two of the most complex and least understood cellular networks known. They are also the subject of groundbreaking, interdisciplinary scientific research by Duke quantitative cell biologist Amy Gladfelter Ph.D.’01.

But one other commonality is key: both fungi and the outermost layer of the human placenta cell are comprised: both fungi and the outermost layer of the human placenta cell are comprised of gigantic cells. The fungi found in a forest can grow as big as their environment. If you look under a forest mushroom, you might see meters or even kilometers of this expansive cell network. On the other hand, a human placenta has one gigantic cell that can be the size of a parking spot when a baby is born.

Gladfelter has been fascinated by such cells for decades. “As soon as I looked under a microscope at these very large fungal cells, I couldn’t stop thinking about them,” she said. “There were so many surprises and paradoxes because most of the rules of cell biology had been established in simple systems, and these cells just kept breaking the rules.” 

Gladfelter’s research approach to the field of medical mycology—studying fungi that cause infections in humans and animals—combines microscopy, machine learning, and computational modeling to analyze giant cell behavior and structure. She is part of a newly formed team of Duke University researchers called Climate and Fungi (CLIF). The group is working to understand how fungal communities develop and what they mean for human health.

The CLIF team hopes to understand how fungi respond to stress, which could help us predict, anticipate and plan for how we might treat fungal pathogens harming humans in the future. Until recently, most fungal infections did not pose a significant threat to human health. But as the planet warms, fungi are quickly adapting to survive at higher temperatures, becoming drug-resistant.

“Duke does a very good job of fostering collaborative projects,” Gladfelter says. “Having the medical school, the engineering school, and arts and sciences in close proximity to one another really helps with interactions. There is a real culture of engagement at Duke. People from different fields are more open to working with one another.”

Gladfelter has also begun to work with AI experts at Duke. One is computational biologist Rohit Singh. She is working with him to unravel how these giant fungal and placenta cells program gene expression. 

This is a new challenge because these giant cells actually have many copies of the DNA spread out and knowing if these genomes cooperate, compete or talk to each other remains a puzzle. 

Another thing giant cell systems have in common is that they’re able to respond to a variety of different stresses extremely well. In the case of forest fungi, these might include drought or disease. In the case of a placenta, these stresses can arise from a conflict between the mother’s physiology and the needs of the developing fetus. For example, there may be low oxygen, or there might be low sugar or nutrients. Because it provides a lifeline between the mother and fetus, the placenta must balance an array of stresses to ensure the delivery of adequate oxygen, nutrients and hormones to the fetus, as well as the removal of carbon dioxide and other waste.

If you think of a cell network as a bustling city center, it might be Shibuya Crossing in Tokyo. This is the world’s busiest intersection where seven crossroads come together, and the lights all turn red at the same time. As many as 3,000 pedestrians can cross safely at the same time. 

The way the crowd moves may seem like complete chaos, yet a very specific set of rules and order govern the activity. These giant cells have similar hubs of activity. Gladfelter works to understand how this seemingly chaotic landscape in a cell gives rise to decisions. Her team also uses chemistry and physics to understand how order emerges in the apparent chaos. They create simulations of molecules to understand how the molecules will assemble. You can’t necessarily directly measure or observe this activity, but computer simulations help make predictions for how molecules may find each other in the complex milleau. 

Using giant cells as a model system has implications for understanding fundamental cellular processes that apply to all cells. Additionally, their work holds relevance for human health, including understanding pregnancy diseases, fungal infections and potentially for understanding cancer, given the presence of giant cells in all these scenarios. 

In these systems, Gladfelter is looking at what goes wrong at the molecular and cellular level. How is cell organization impacted by stress? How is that stress patterned in space? How does the size of the cell and the shape of the cell impact how a stress is reacted to, like how cells respond to stress? 

“These giant cells help bring us new ways of thinking about cell organization and disease,” she says. “This science will help us attack disease with a completely new lens than has historically been used.”