A defining feature of the cell is the cellular membrane, a physical barrier that separates the cell from its environment and defines its compartments. The membrane is embedded with many mini-machineries (membrane proteins) that transport molecules such as ions, water, and sugars across the membrane and sense external signals such as light and chemicals. Although these machineries are common causes as well as therapeutic targets of human diseases, almost nothing is known about many of them, sometimes even their existence. Hui Sun has been studying enigmatic membrane machineries that had not been known to exist previously or had eluded identification.

While he was an associate in the lab of HHMI investigator Jeremy Nathans, Sun studied a membrane transporter that was defective in patients with Stargardt disease, an inherited condition that leads to sudden vision loss early in life. Although the Stargardt disease transporter is most similar to a protein involved in cholesterol transport, its sequence information provided no clue about what it might transport and why its mutations lead to sudden vision loss. Using Stargardt disease protein purified and reconstituted from photoreceptor cells, Sun provided biochemical evidence that the cause of this disease is defective transport of a vitamin A–derived chemical. This finding was surprising because the existence of such a transporter had not been predicted.

While studying another vision disease, called Best macular dystrophy, Sun and colleagues identified a new family of anion channels in vertebrate and invertebrate animals. This new channel family is unlike any known membrane receptor, transporter, or channel.

When Sun set up his lab at the University of California, Los Angeles, he decided to tackle a long-standing question about vitamin A transport: How does vitamin A—a molecule essential for the eye, brain, immune system, reproductive system, and developing embryo—get specifically transported to tissues that depend on it? Evidence gathered over three decades pointed to the existence of a cell-surface receptor capable of binding the vitamin A carrier protein in the blood and mediating the transport of vitamin A into the cell. But this mysterious receptor had never been found. Sun suspected two likely obstacles: the fleeting interaction between the carrier protein and its receptor and the fragility of the receptor itself. After trying several strategies, his lab developed a technique that overcame both obstacles and, using hundreds of bovine eyes, eventually purified and identified the long-sought receptor. Human genetic studies have shown that mutations in this receptor cause a wide range of pathological phenotypes that affect many organs such as the eye, brain, heart, and lung. Since the discovery of this receptor, Sun's lab has developed new sensitive techniques to reveal how this membrane receptor functions to absorb vitamin A. Surprisingly, its mechanism is unlike any previously characterized membrane receptor, transporter, or channel.

These experiences have made Sun appreciate the complex nature of membrane receptors and transporters in biology and medicine. His lab is continuing to develop new techniques to study known and previously unidentified membrane receptors and transporters that are potential therapeutic targets in treating human diseases.