Cell Death Processes Are Reversible

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In 2007, Ho Man “Holly” Tang took a break from her undergraduate biology studies at Iowa State University to join her older brother, Ho Lam “Hogan” Tang, then a doctoral student at the Chinese University of Hong Kong, to work on a project together. In Ming-Chiu Fung’s immunology lab, Hogan had been investigating how disturbances in the cytoskeletons of cells might contribute to the fragmentation of mitochondria during apoptosis, the most familiar form of cell suicide. But the siblings had a more fundamental question: Can cells recover from the cellular chaos that ensues once apoptosis is initiated?

There are many different triggers of apoptosis, but they all ultimately activate executioners called caspases. Cleaving hundreds of different kinds of proteins within a cell, these enzymes wreak havoc on the genome, attack structural proteins composing the cell’s organelles, and dismantle the cytoskeleton, leading cells to shrink, bleb, fragment, and seemingly die. “At that time, and even now, the general dogma was that apoptosis is irreversible,” Hogan (hereafter, Tang) recalls. “Holly and I were very curious and asked, ‘Is this really true?’”

The Tangs exposed a variety of human cancer cells to toxins such as ethanol and waited for long-established signs of apoptosis, such as caspase activation and cell shrinking. Next, instead of throwing away the “dead” cells at the end of the experiment, “we washed and incubated them with fresh medium overnight,” says Tang.

It doesn’t seem to matter how apoptosis started. If good conditions are restored, anastasis can rescue cells following a variety of insults.

“Surprisingly, some cells had regained normal morphology when we looked at them the following morning.”1 The siblings named this phenomenon anastasis. Apoptosis means “falling” in Greek, and the process facilitates the natural turnover of cells, akin to petals falling from a fading flower or leaves from a tree in autumn. Anastasis, on the other hand, means “rising,” and in Christianity refers to the resurrection of Jesus.

The research community was initially skeptical that cells could come back from the dead. “Our finding was quite controversial—one of our first few papers got rejected more than 11 times in three years,” says Tang, now a molecular and genetic biologist at Johns Hopkins University.

He got more experimental support for anastasis after he joined the lab of Denise Montell, a cell and developmental biologist then at Johns Hopkins. In collaboration with his new lab, former colleagues in China, and his sister, who had followed him to Baltimore after completing her master’s degree at Iowa State, Tang conducted experiments not only on human cancer cell lines, such as HeLa, but also on normal, cultured mouse liver, rat heart, and ferret brain cells, as well as multiple cultured human cells, including fibroblasts.2 Time and again, the cells appeared to recover from late-stage apoptosis, even after suffering DNA damage and cell fragmentation. “The moment I really knew there was an important phenomenon was when we made a movie of an entire field of human lung cancer cells shriveling up and blebbing and then recovering,” says Montell, now at the University of California, Santa Barbara. “It was striking.”

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Friday, February 1, 2019