Why We Do It
“Going too far is as bad as falling short” — this ancient Chinese saying from The Analects of Confucius1 reminds us that moderation is key in all things. Balance is essential, and this holds true even for life’s most fundamental processes. Phosphate, one of the vital elements necessary for life’s growth, can become toxic if it accumulates excessively in cell. Maintaining cellular phosphate levels within a reasonable range is crucial for the proper growth and development of bodies. When it comes to excessive phosphate buildup, you might recall the 15th-century Dutch painter Hieronymus Bosch’s famous oil painting, The Extraction of the Stone of Madness2, in which a doctor attempts to remove a “stone of madness” from a patient’s brain—believed to be the cause of the patient’s ignorance. It wasn’t until 1930 that German doctor Karl Theodor Fahr reported that similar “stones” of calcium phosphate could actually be found in the brains of patients with brain disorders. On a molecular level, the only known transporter in the human body capable of removing excess phosphate out of cell is XPR1. This transporter helps expel surplus phosphate from cells, maintaining phosphate homeostasis and preventing the formation of “stones of madness.” The chemical process at play here serves as a window into ancient wisdom, drawing us into deeper exploration.
An Unexpected Finding
By analyzing the chemical structure of XPR1, we gradually realized that this ancient molecule may play a far more complex and unique role in cells than we initially thought. While it is usually defined as a transporter that moves substances across membranes according to the alternating-access model, a closer look at its structure suggested that it might actually facilitate phosphate transport in a channel-like manner.
This discovery sparked an overwhelming sense of excitement among our team of young researchers. We decided to start from scratch and create a purely functional analysis system. After countless attempts and explorations, we succeeded in building a protein-lipid vesicle-based experimental platform to test the ability of XPR1 to transport phosphate. Through our experiments, we confirmed that XPR1 not only efficiently transports phosphate but that its transport characteristics indeed exhibit channel-like features. Simultaneously, through collaboration with Professor Yong Wang, we conducted extensive molecular dynamics simulations to vividly reproduce the process by which XPR1 transports phosphate in a channel-like manner.
On the journey to uncover ancient tales, the cold winds outside could never extinguish the fire of passion burning within.
Dr. Wenhui Zhang and Dr. Yanke Chen, two smiles that light up the path ahead.
What’s Next
We have made significant progress in understanding the mechanism of XPR1 in relation to the formation of “stones of madness” in the brains of patients with brain calcification. Moving forward, we aim to further explore XPR1’s role under various physiological and pathological conditions, particularly how it interacts with other molecules to maintain cellular homeostasis. Based on these findings, we hope to develop targeted drug molecules that can provide new treatment strategies for patients, ultimately turning the frightening “stones of madness” in the brain into a thing of the past.
References
- The Analects of Confucius (from the Chinese Classics). James Legge (Translator).
2. https://en.wikipedia.org/wiki/Cutting_the_Stone.