Asking the Hard Questions: A Profile of Xiang-Lei Yang

Xiang-Lei Yang was at a cruising altitude of 30,000 feet last October on a flight to Hong Kong when she received an unexpected email. It was a message from a woman named Crissy, whose daughter suffers from an untreatable neurological disease called Charcot-Marie-Tooth (CMT).

Yang, a professor at The Scripps Research Institute (TSRI), and her colleagues had just published a paper in journal Nature on CMT. They had discovered how a mutant protein interacts with the nervous system to cause a subtype of the disease—an important step in developing therapeutics.

“This is such a ray of HOPE!!!” wrote Crissy in her email. Her daughter had been diagnosed with the disease three years before, and there wasn’t much doctors could offer.

As Yang read the email, she was struck by this sudden, personal connection. “She was so warm,” said Yang. “That was the first time I’d experienced anything like that. The sense of gratitude and the sense of hope in this email was very moving.”

The Trouble with CMT

CMT—the most common heritable neurological disease—strikes about one in 2,500 people. Symptoms tend to appear in childhood.

On the surface, the signs of CMT are obvious. The disease attacks the peripheral nervous system, causing numbness in the feet and hands and trouble balancing and walking. Patients with CMT subtype 2D (CMT2D), like Crissy’s daughter, have particularly difficult time with fine motor skills, such as buttoning a shirt.

What has been much harder to see is how CMT works at the molecular level—an important prerequisite for scientists to design therapies. To add to the puzzle, genetic sequencing usually turns up an array of mutations in people with CMT, making it difficult to identify the biological underpinnings of the disease.

To better understand CMT and normal physiology, Yang has combined biochemistry with two techniques in structural biology, called x-ray crystallography and hydrogen-deuterium exchange (HDX) analysis, to create 3D models of important proteins. She has set her sights on a family of enzymes called aminoacyl-tRNA synthetases, which appear mutated in some forms of CMT.

In her office, Yang has a 3D-printed version of one kind of tRNA synthetase. She can hold it up, study it and picture how it interacts with molecular partners. “It gives you a sense of direction,” said Yang. “This, in my mind, is like a map.”

Charting a Course

On a more traditional kind of map, Urbana, Illinois is an island in a sea of corn fields. The winters are icy—but the science is hot, with 23 Nobel Laureates having passed through the city’s branch of the University of Illinois.                            

It was there that Yang learned to use different techniques to solve biological structures, such as proteins and DNA, as she earned her PhD in biophysics and computational biology under the guidance of Professor Andrew Wang.

In 2000, Yang arrived at the California campus of TSRI as a postdoctoral researcher in Professor Paul Schimmel’s laboratory. That’s when Yang first encountered the tRNA synthetase family.

This family is a bit of biological curiosity. For years, it was known that the 20 enzymes in this family helped with protein synthesis. This function existed in lower organisms, such as roundworms, and higher organisms, such as humans. In fact, their function in protein synthesis had been “conserved” through eons of evolution, designating tRNA synthetases as “ancient” enzymes.

But, just a year before Yang arrived, Schimmel and his former lab member Keisuke Wakasugi discovered that a member of the human aminoacyl-tRNA synthetase family, called tyrosyl-tRNA synthetase (TyrRS), had additional functions. The researchers found that part of the enzyme could function to attract immune cells and to stimulate blood vessel growth. “That was a really exciting time for tRNA synthetase research,” Yang said.

What else could tRNA synthetases do?

“When I started my lab, I decided that would be my focus,” said Yang.

Impact on Disease

Yang joined the TSRI faculty in 2005 and continued to work closely with Schimmel.  They even teamed up to co-found biotech company aTyr Pharma, which focuses on developing tRNA synthetase-related molecules as drug therapies.

Over the years, it has become clear that tRNA synthetases play a number of important roles.                                                                          

“They can fight cancer, they can sense stress in our cells and they can protect our DNA,” said Yang. “When they are mutated, they are involved in a wide range of diseases.” Such as CMT.

In their paper published last fall, members of the Yang laboratory and collaborators at The Salk Institute for Biological Studies focused on a member of the tRNA synthetase family called glycyl-tRNA synthetase (GlyRS), which is altered in people with disease subtype CMT2D.

The team’s structural biology work proved crucial in understanding how mutated forms of GlyRS cause disease. Previous studies from the Yang lab had shown the mutated GlyRS has an odd shape—its molecular structure opens up to reveal binding components inside. The new research showed that this open form can bind to a receptor on the surface of the cell and block the signals of an important growth factor, which then stops a signal crucial to maintaining nerve health.

Shutting down that signal is like cutting power to a city block. No wonder people with mutated GlyRS have trouble sending and receiving signals from their hands and feet.

“This paper is the first molecular mechanistic understanding of CMT2D,” said Yang.

Interestingly, Yang and her colleagues found that reintroducing the blocked growth factor through gene therapy could reverse some CMT symptoms in mouse models of the disease.

There’s still a lot to learn about tRNA synthetases. Outside of CMT, recent studies suggest that tRNA synthetases may be important for vascular health. Another study on GlyRS, published by Yang and colleagues in June 2016, shows that that future therapies might also target this protein to halt cancer growth.

It could have been simple—accepting the common wisdom that tRNA synthetases were part of protein synthesis and there was no more to them. But Yang and her colleagues were willing to ask tough questions that opened the doors to discovery.

“You anticipate, or you hope, that you will discover something new,” said Yang. “That possibility exists every day.” 

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