Ke Xu: Navigating between worlds

Ke Xu comfortably navigates between different worlds—geographic, cultural and scientific.

He was born in 1982 in the city of Ya’An, where the Tibetan Plateau meets the Chengdu Plain in the center of Sichuan Province, about two hours’ drive from the booming city of Chengdu.

Xu left Ya’An when he was six years old and moved to one of China’s largest cities, Chongqing. His father had been a graduate student there while the family lived in Ya’An, and both his parents had been appointed English professors at Chongqing University.

When he was 11, his parents temporarily moved to Nanjing to teach, while Xu went to Beijing to live with his grandmother. When he was 14, his parents came to Beijing to teach at Tsinghua University. Xu lived in campus housing with them and remained at Tsinghua for his undergraduate studies.

Tsinghua University is located in the university sector of NW Beijing, near the Summer Palace. Founded in 1911 on the grounds of an old royal garden, the university survived the tumult of WWII and the Cultural Revolution. Known as one of best universities in China, it educates 31,000 students on its 980-acre campus. Xu studied chemistry and graduated with a B.S., with highest honors, in 2004.

For graduate school, Xu flew across the Pacific Ocean to attend Caltech in Pasadena. It was the first time he had been outside of China. At Caltech he joined the lab of Jim Heath, a former Miller Fellow in chemistry at Berkeley who had worked with Rich Saykally. In Heath’s lab Xu planned to do research in chemical physics.

“It was an interesting time to be in Heath’s lab,” says Xu. “He did his Ph.D. at Rice University with Smalley and Curl, where his work helped them win the Nobel Prize for the discovery of C60 and other new forms of carbon called fullerenes. Yet as a mid-career scientist Heath switched gears and began to work on biology. That encouraged me to think I could make the switch as well.”

Xu wrote his award-winning Ph.D. thesis on the nonlinear electrical properties of one-dimensional nanostructures. Then for his postdoc he decided it was his turn to jump into the realm of biology. In 2009 he joined the lab of Xiaowei Zhuang, a Howard Hughes Medical Institute (HHMI) investigator and professor at Harvard University. Zhuang had developed an imaging technique, stochastic optical reconstruction microscopy (STORM), that explored the inner workings of cells at the nanoscale and single-molecule levels. STORM is just one of many techniques that have become available since researchers developed super-resolution fluorescence microscopy in the 1990s.

Visible light spans the electromagnetic spectrum between red at 700 nanometers to violet at 400 nanometers. “Because of the diffraction effect,” says Xu, “it’s very difficult to use even the best optical microscopes to see objects smaller than the wavelengths of light. But by using advanced STORM techniques, we are able to resolve objects below 10 nanometers in size, about the size of many proteins and other biomolecules.”

To visualize how this works, imagine a large public Christmas tree like the one at the White House in Washington, DC, or in Union Square in San Francisco. The tree is covered with an interesting pattern of strings of closely spaced LED lights. Each string has its own unique color. All of the LED lights are blinking at random.

You want to document how the strings of lights were strung on the tree, but you only have an older low-resolution black-and-white digital camera. If you snap a single photo, all you can see is the outline of the tree and a random pattern of blurry pixels of white.

However, if you were extremely patient, you could stand there and snap hundreds of photos of the tree. Then, for each image, you could carefully plot the center point of the blurry dot. Finally, you could superimpose all the images together digitally to reconstruct the original pattern of lights and reveal their structure.

At a nanoscopic scale, STORM operates in a similar fashion. Individual biomolecules are labeled with fluorescent dyes, which are switched on and off with a laser. By recording the location of the fluorescence signals as they are turned on and off, the positions of hundreds of thousands of molecules can eventually be determined.

Using these techniques during his postdoc, Xu revealed with exquisite detail the structure and molecular composition of axons, the tube-shaped structures that transfer signals from one nerve cell to the next, and to muscle and other cells.

“Like many cells,” says Xu, “human nerve cells have very distinct structures and depend on these structures to function properly. Understanding how nerve cells work, and the diseases that result when they fail to work, requires the ability to image their nanoscale structures.”

Xu joined the Berkeley chemistry faculty in 2013 and has been extending STORM by integrating it with the cornerstone of physical chemistry—spectroscopy. Many images of the nanoscale realm use false colors created after the fact to distinguish features. To return to our analogy of the Christmas tree, the black-and-white images could be artificially colored—one string colored red, another green—to help us tell them apart.

Xu developed a new technique to directly resolve the subtle nuances of color in STORM images, this time by directly recording the full fluorescence spectrum of every single molecule. He tagged different molecules with separate fluorescent dyes, each dye emitting a slightly different color when illuminated by a laser. By recording and resolving the wavelengths of each single molecule as the molecules individually light up one after another, he was able to reveal the different structures inside the cells in true color. In our Christmas tree analogy, this would be similar to replacing the black-and-white camera with a more modern color version.

To demonstrate the power of this new technique, he simultaneously imaged four subcellular features tagged by four red dyes that are highly similar in color—and was able to clearly discriminate them from each other with excellent spectral and spatial resolution. His lab is now combining this new technique with dyes that change color in different environments to report, with ultrahigh resolution and sensitivity, changes in local pH, viscosity and other aspects of living cells.

Xu has dubbed his new true-color technique SR-STORM (spectrally resolved STORM). And if that breakthrough is not enough, the Xu group has also developed a technique for using electron microscopy to help confirm their results on wet and untreated whole cells.

Explains Xu, “Electron microscopes use beams of electrons, not light, to create images. This means they can resolve details at the nanoscale with ease. However, the samples have to be dehydrated because the imaging takes place in a high vacuum. This drying process destroys some of the structural details that we were hoping to see.”

The Xu group’s solution was to cover the sample with a single-atom-thick film of graphene, a flat layer of carbon atoms arranged in hexagons. Since the graphene is impermeable, it allows cells and other biological structures to remain in their native hydrated state.

These images demonstrate Xu’s new method, spectrally resolved stochastic optical reconstruction microscopy (SR-STORM). Fluorescent tags on individual biomolecules are switched on and off with a laser, and their signal is passed through a prism, allowing both their position and their unique spectrum to be simultaneously determined.

Adds Xu, “Using this approach, we can perform both STORM and electron microscopy on the same wet samples, which allows us to correlate the results and confirm the details of the structures we are imaging.” 2016 has been a good year for Xu. Chemical and Engineering News took note of Xu’s accomplishments and included him in their Class of 2016 “Talented 12.” According to the magazine’s editors, their feature story “blows the covers of a group of topnotch chemistry ‘operatives’ whose mission it is to solve some of the world’s most diabolical scientific problems.”

In addition, along with College of Chemistry colleague Markita Landry, Xu was one of eight researchers nationally to receive the 2016 Beckman Young Investigators Award. Earlier in the year he won an NSF CAREER Award and was elected a 2016 Sloan Research Fellow. Most recently, Xu was also one of 18 researchers nationally to win a 2016 Packard Fellowship.

For a young man who never set foot outside of China until he left for grad school, Xu has shown himself to be a true pioneer and has quickly made a new home here in the College of Chemistry.