Of mice and zebrafish: How scientists solved a decades-old mystery and uncovered new insights about inflammation
Sometimes you can solve a mystery with a fish but not a mouse. Sometimes you can see a biochemical process happening, but you can't study it in detail until you identify the underlying players. Sometimes separate streams of inquiry turn out to be part of the same story.
In a groundbreaking study published in Nature, scientists at Memorial Sloan Kettering Cancer Center (MSK) have solved a decades-old mystery and gained new insights into the inflammatory signaling pathway. The research, led by Dr. Yanan Ma and Dr. Philipp Niethammer, reveals that a critical enzyme, previously unidentified, plays a crucial role in both summoning immune cells to fight infections and protecting healthy cells from immune-induced damage.
The discovery began in 1992 when scientists at McGill University studied a fatty signaling molecule called 5-oxoETE, which is responsible for summoning immune cells to infection sites. They identified the enzyme but struggled to pinpoint its genetic basis, as they lacked the knowledge of the human gene encoding the enzyme. This limitation hindered further investigation into the enzyme's role in disease and its potential implications.
Dr. Ma, a postdoctoral researcher in Dr. Niethammer's lab, and Dr. Hui, a former labmate, used zebrafish as a research model to overcome the limitations faced in mice. Zebrafish share about 80% of their genes with humans and lack the receptor needed to detect 5-oxoETE. By systematically silencing candidate genes in human cells and observing the enzyme's activity, Dr. Ma identified the gene DHRS7 as the one responsible for producing the enzyme.
The findings shed light on how the body responds to inflammatory signals. When 5-oxoETE binds to its receptor, specialized immune cells called neutrophils are recruited to the site of infection, where they deploy toxic substances to eliminate harmful bacteria. However, excessive inflammation can cause damage to healthy cells. The enzyme discovered by Dr. Ma and her colleagues ensures that the inflammatory response is tightly regulated, preventing unnecessary damage to healthy tissues.
This discovery has significant implications for understanding and treating diseases characterized by uncontrolled inflammation, such as cancer, inflammatory bowel disease, and asthma. By targeting the enzyme or its genetic basis, researchers may develop new therapeutic strategies to manage these conditions effectively.
The study exemplifies the power of interdisciplinary collaboration and the importance of choosing the right research model. By leveraging zebrafish as an alternative model to mice, the MSK team was able to uncover a critical piece of the inflammatory signaling puzzle. The findings not only resolve a long-standing mystery but also open up new avenues for research and potential treatments for a range of inflammatory diseases.
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