BOZEMAN — A molecular geneticist at Montana State University has discovered a cellular process once believed impossible by scientists – the creation of the amino acid cysteine within a living cell when the cell's primary systems to do so fail. The discovery may one day lead to new cancer treatments.
The findings were published May 21 in the scientific journal Nature Chemical Biology, which is available online .
"All cells need a constant supply of an amino acid called cysteine in order to stay alive," said the paper's lead author Ed Schmidt, a professor of genetics and development in the Department of Microbiology and Cell Biology in MSU's College of Agriculture . "Yet cysteine is not available outside of the cells."
Cysteine is critical to cells because it helps them build proteins and defend against damage. It also enables formation of disulfide bonds, which stabilize proteins to help cells keep their three-dimensional shape. Researchers have known for decades that cells have no access to cysteine externally, thus they must create it internally by chemically splitting an oxidized form of it – called cystine – to obtain the amino acid they need to survive. This process is called a disulfide reductase system.
"Scientists long believed this process was absolutely essential for all living cells," Schmidt said. "However, we have discovered a previously unknown system in mammalian cells that can take over when the main systems fail."
This discovery was made in three stages over a nine-year period. The first "aha moment," Schmidt said, came in 2014, when a colony of mice survived when they, based on the science at the time, should not have been able to. This is because they had no known system to convert cystine into cysteine.
"This was supposed to be impossible," he said. "No living organism or cell had ever been found that could live without having a functioning disulfide reductase system."
This discovery was not happenstance. Schmidt had already genetically engineered mice to individually lack one or the other of the two primary disulfide reductases in the liver.
"Some of the physiological responses we were seeing in the livers of each of those mouse lines suggested to me that the belief that no cell could live without having at least one of these two reductases might not be correct," he said. "I wanted to test this."
It took seven years for Schmidt and his team, in partnership with the team of his collaborator Peter Nagy from the Hungarian National Institute of Oncology in Budapest who brought unique analytical capabilities to this project, to uncover how the mice were still making cysteine from cystine without having a disulfide reductase system in place. It turns out, when cells cannot use a disulfide reductase system to obtain cysteine, the backup system chemically severs an adjacent carbon-sulfur bond in the cystine, ultimately releasing cysteine for the cell to use.
This newly discovered backup system, he said, might help humans survive by protecting cells from electrophilic toxins. Many electrophilic toxins are organic molecules that some organisms make to kill other organisms that would otherwise eat them.
"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," Schmidt said.
Notably, this backup system might also help some cancer cells survive exposure to chemotherapies, radiation therapies or immune therapies.
"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."
Several MSU students, some of whom have since graduated, coauthored the paper, including co-first authors Zoe Seaford and Sydney Austad, who did their work as undergraduate students in Schmidt's lab. Martina Serrano Alvarez and Reed Noyd were also undergraduate students in the lab when they participated in the project, and Colin Miller was a doctoral student. Other scientists and trainees from various institutions also collaborated on portions of the research presented in the paper.
"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 the agricultural college. "I congratulate Dr. Schmidt and his team for their exceptional achievement and for engaging students as true partners in research that delivers global impact."
Schmidt joined MSU in 1999. His research interests include gene regulation, cell and organismal physiology, mouse genetics, embryology, biochemistry, metabolism and laboratory mice whose DNA have been genetically altered by inserting one or more genes from another organism into the mouse genome.
