Biophysics, Structural Biology
The University of Texas Southwestern Medical Center
Dr. Jiang is also a professor of physiology at the University of Texas Southwestern Medical Center.
Ion Channels and Transporters
Scientific late bloomers of the world, take hope from Youxing Jiang.
Despite a stellar record at Peking University and acceptance into Yale's graduate school, Jiang admits "I had no idea what I wanted to do." But thanks to a fortuitous lab rotation at Yale, Jiang came face-to-face with his scientific calling: using x-ray crystallography to decipher the structures of critical proteins. "Nice pictures. So cool. I fell in love with protein x-ray crystallography."
The technique is a highly challenging yet artful way of using x-rays to determine molecular structures in three dimensions. First, a beam of x-rays is sent speeding toward a crystal made up of countless molecules arranged in an ordered manner. Depending on the size and arrangement of these molecules in the crystal, the x-ray beams bend in unique patterns that can be captured and used to reconstruct what the molecule looks like. As a postdoctoral fellow for Nobel laureate Roderick MacKinnon, an HHMI investigator at the Rockefeller University, Jiang honed his skills in x-ray crystallography by studying ion channels. These molecules form pores that allow ions to pass across cellular membranes and regulate essential processes such as controlling the pace of the heart and regulating the secretion of hormones into the bloodstream.
"Initially, I didn't know how tough membrane protein structure determination would be. These molecules are very unstable and difficult to work with, and my first three years as a postdoc represented a period of suffering and frustration," Jiang recalls of his time in MacKinnon's lab. But Jiang's hard work and intuitive understanding of experimental design paid huge dividends. By the time he was ready to leave the postdoctoral nest, he had authored seven papers, including four in the journal Nature.
Today, Jiang runs his own lab at the University of Texas Southwestern Medical Center, and ion channels remain his focus. Jiang doesn't mind occasionally challenging the interpretations of more senior scientists. "I am a risk taker," he acknowledges. "I have very conservative projects and very risky projects and am willing to try all means to make something work."
Jiang also admits that pretty pictures of ion channel structures are just the beginning. Even though they can reveal information in astonishing detail, the challenge is to put them in the context of a working machine. "A nice picture is very telling, but we cannot be limited to only producing structures. That's just a snapshot. Their true potential is only realized in combination with supporting experiments." To do that, his lab also uses traditional biochemical and electrophysiological tools to understand their target molecules.
Like switches on a battery for the cell, ion channels harness electrical currents from the store of charged particles, the ions, in cells by regulating their flow across cell membranes, all on the order of milliseconds. But not just any ion can get in; ion channels are selective about the type of ions they allow to come and go. Seeing the fine print of ion channels is important, Jiang argues, because they are the foundation of the cellular electrical grid that regulates the pace of the heart, the flexing of muscle, and the firing of nerve impulses. Dysfunctional ion channels are implicated in a variety of medical conditions, including heart arrhythmias, cystic fibrosis, diabetes, hypertension, and neurological and psychiatric diseases. As a result, Jiang notes, ion channels are important drug targets, and knowing their structure and mechanism of action can aid in the design of more effective medicines.
When Jiang gets his hands on a new picture of the coiled, ribbon-like structure of a protein, he zeroes in on its telltale architectural novelties. "That's something I always want to see, something different, something unique, something unconventional," Jiang says. "Proteins are all different. A different structure can give it a different job." To understand the principles that allow these molecules to function the way they do, "you really need those pictures."
As an HHMI investigator, Jiang will try to tackle the big question of how ion channels are optimized to work for only certain types of ions. He and his group want to visualize the molecular features that allow ions of different sizes to squeeze through the channel pores. "We do need more structures," Jiang says. "In my field, there are a lot of fundamental questions that still need to be addressed."
For someone who was once unsure of his calling, Jiang now has a vision as sharp as the pictures that emerge from his lab. He wants to sate an appetite for the "biggest and most interesting questions" in his field.
"If we can show something so fundamental and basic that it gets into the textbooks, then I'll know our work is up there."