Researchers at Memorial Sloan Kettering Cancer Center have identified a human gene that resolves a 30-year-old mystery about how the immune system prevents its own defenses from damaging healthy tissue.
The mystery began in 1992 when scientists discovered an enzyme that produces and breaks down a fatty signaling molecule called 5-oxoETE, which attracts immune cells to fight infections. Researchers could not identify the human gene responsible for making the enzyme, blocking progress for decades.
Postdoctoral researcher Yanan Ma, working in the laboratory of cell biologist Philipp Niethammer, finally identified the gene, called DHRS7, by systematically disabling candidate genes in cultured human cells. When Ma disabled DHRS7, the enzyme stopped functioning.
The breakthrough relied on an unconventional choice of model organism. While mice typically serve as the standard in biomedical research, they lack a receptor capable of recognizing 5-oxoETE. Zebrafish retain this biological machinery, allowing Ma's team to study the complete signaling process.
"This means that you can't study the pathway in mice," Dr. Ma says. "But the pathway is intact in fish. So picking the right alternative model was critical to advancing our understanding of how the human body responds."
In separate experiments, postdoctoral researcher Miklos Lengyel used zebrafish to study colitis. When he removed the gene for the receptor that recognizes 5-oxoETE, zebrafish developed intestinal inflammation without infection, suggesting the pathway has protective functions beyond simply activating immune responses.
The findings, published October 7 in Nature, could advance research into cancer, inflammatory bowel disease, and asthma. They raise the possibility of developing treatments that strengthen the body's natural defenses against inflammatory damage.