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ChEM-H seed grant sparks postdoc collaboration in cell death

Jennifer Cao and Cole Dovey met at the Stanford ChEM-H Postdoc Retreat and discovered that they shared an interest in cell death pathways.

In 2015, postdoctoral scholars Jennifer Cao and Cole Dovey met at the Stanford ChEM-H Postdoc Retreat and discovered that they shared an interest in cell death pathways. Funding from Stanford ChEM-H has brought their labs closer to understanding the different ways cells self-destruct.

Jennifer Cao and Cole Dovey were interested in death. So interested that you might say that death was in their DNA. In March 2015, Cao and Dovey, then postdoctoral scholars in the labs of Scott Dixon and Jan Carette, respectively, met at the Stanford ChEM-H Postdoc Retreat and started chatting. The pair, which shared a fascination in the ways cells self-destruct, had a lot to talk about. With support from a Stanford ChEM-H seed grant, they used the chemical and genetics resources and expertise of their labs to uncover some of the mysteries behind largely unexplored cell death pathways. The collaboration between their labs, which has already resulted in two publications, continues to tackle these questions today.

Photo of Deadly Constellations
"Deadly Constellations." For millennia, humans have looked to the stars when contemplating our existence. Our studies reveal that cells, life's most basic unit, make life-or-death decisions based on 'constellations' of inositol molecules—depicted here in the night sky. A gathering of the dead unfolds while the still living gaze upward to discover their fates “written in the stars.” Watercolor painting by Graham McLeod; Design by Graham McLeod and Cole Dovey

Controlled cell death is a vital part of normal embryonic development and the destruction of disease-afflicted cells, but too much or too little cell death can mean disaster. With better understanding of why, when, and how cells self-destruct, scientists could use cell death signaling molecules as diagnostic markers or as switches to turn cell death on or off.

Until recently, a lot of the research in cell death focused on the best characterized form of it, called apoptosis. In this kind of cellular suicide, molecular messengers called caspases are activated and trigger the degradation of cells by cutting up proteins, killing the cell from the inside out. In the last two decades, researchers have started to learn about cell suicide pathways that rely on other kinds of signals.

Those non-apoptotic pathways quickly came to the forefront of Cao and Dovey’s conversation. Cao had been pulling apart ferroptosis, an iron-dependent process, while Dovey had zeroed in on necroptosis, a kind of cell death that involves the insides of the cell leaking out through an expanding, ballooning membrane.

“Both ferroptosis and necroptosis are important clinically,” explains Cao, “either to therapeutically target and destroy cancer cells, or to prevent unwanted cell death in the case of neurodegeneration and inflammation.” The problem was that they needed to know more about the chemical cues and genes involved in activating or dampening the processes.

Cao and Dovey were granted funding through the Stanford ChEM-H Postdocs at the Interface program, then in its first year. This seed grant funds collaborative research between postdocs to answer questions at the interface of chemistry, biology, and medicine that could have big implications for human health. The team’s complementary expertise and strategies let them attack cell death from multiple angles.

“The benefits of the collaboration were immediate,” says Dovey. “Because we had been taking different approaches to related problems in biology, we could quickly draw upon the diversity of insights and perspectives from each of our labs to accelerate our work.”

Cao leveraged the Carette’s lab expertise to conduct a screen, looking for genes that were either more or less active in ferroptosis. They found that a gene that codes for an efflux pump, a channel that moves drugs from the inside to the outside of the cell, makes cells more vulnerable to ferroptosis-inducing agents. This same pump is also associated with some drug-resistant cancers, suggesting that inducing ferroptosis could kill cancers that are conventionally difficult to kill.

The collaboration also empowered Dovey with new tools and ideas as he pursued MLKL, the presumed executioner protein in necroptosis. With Cao’s support, Dovey found that while an inactivated form of MLKL is harmless and often present in cells, it is unleashed through a series of steps that depends on a code of small molecules. Only when this so-called “death code” is dialed correctly does MLKL cue the destruction of the membrane, causing the cell to spill out its contents.

“The flow of information, exchange of ideas, and synergy between the labs was incredible,” says Cao. So incredible that the labs continue to work together though the two postdocs have since transitioned into new roles. Cao is now a Senior Scientist at Pharmacyclics/AbbVie developing cancer drugs for patients, and Dovey has accepted a Visiting Assistant Professorship at Colorado College.

Jan Carette, Associate Professor of Microbiology and Immunology, and Scott Dixon, Assistant Professor of Biology, are both Faculty Fellows at Stanford ChEM-H.