How did the impossible mice survive?

The finding unfolded in three stages. The first clue came in 2014, when a colony of genetically engineered mice survived under conditions that, by the scientific understanding of the time, should have killed them. The animals lacked every known mechanism for converting cystine into the cysteine their cells required.

"This was supposed to be impossible," Schmidt said. "No living organism or cell had ever been found that could live without having a functioning disulfide reductase system."

The result was not a lucky accident. Schmidt had already engineered mice whose liver cells lacked one or the other of the two main disulfide reductases, and the physiological responses he saw in those animals made him doubt the textbook assumption. He set out to test it directly.

Explaining the survival took another seven years. Schmidt's team collaborated with Peter Nagy and his group at the Hungarian National Institute of Oncology in Budapest, whose analytical tools revealed how the cells were still extracting cysteine from cystine.

What is the backup pathway?

The answer is an alternative chemical route. When the usual disulfide reductase pathway is unavailable, the backup mechanism breaks an adjacent carbon–sulfur bond within cystine. That reaction ultimately frees cysteine the cell can use.

Schmidt suspects this system evolved in early multicellular organisms as a defense against electrophilic toxins — reactive molecules produced by other organisms as chemical weapons against predators or competitors. "The ability of our cells to survive, at least for a time, without disulfide reductases, likely evolved in our earliest multicellular ancestors as a mechanism that allowed these organisms to resist being killed by electrophilic toxins made by the things they ate or the things found in their environment," he said.

Could this make cancer therapy work better?

The pathway has a darker side. Researchers suspect some cancer cells may use it to survive chemotherapy, radiation therapy or immune therapy, all of which work by stressing or damaging tumors.

"This same pathway that protects our cells from oxidants or toxins also likely protects cancer cells from therapies," Schmidt said. "Now that we know they have this defense mechanism, we might be able to precisely disable it in cancers, making them more susceptible to cancer therapies, as well."

Any clinical application remains speculative for now. The study shows the pathway exists and how it works in cells; selectively blocking it in tumors without harming healthy cells that may also depend on it is a separate, unsolved challenge.

Who did the work?

Several MSU students drove the research. Zoe Seaford and Sydney Austad served as co-first authors as undergraduates in Schmidt's laboratory. Martina Serrano Alvarez and Reed Noyd also participated as undergraduates, and Colin Miller contributed as a doctoral student. Scientists from several other institutions collaborated on portions of the work.

"This scientific breakthrough underscores the power of research to redefine what we thought was possible and advance new approaches to cancer treatment," said Sreekala Bajwa, dean of MSU's College of Agriculture. Schmidt, who joined the university in 1999, studies gene regulation, metabolism and genetically modified mice.