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Xiaowei Zhuang

Xiaowei Zhuang likes knowing little. That way, she has room to learn a lot. Over and over, she has combined her passion for exploration with a knack for identifying technical problems whose solutions offer far-reaching impacts.

Zhuang has not just conquered methodological challenges and handed off the tools and techniques she’s developed. She has repeatedly mastered monumental amounts of material in unfamiliar fields and then applied her innovations to these areas. Her fearlessness and talents have fueled numerous moonshots into life’s nanoscale terrain. She has illuminated a plethora of biological phenomena, thus unveiling the architecture that allows molecular machinery to perform crucial physiological tasks and discerning how different types of cells coordinate to enable tissue function.

Zhuang grew up in a scientific household. Both of her parents were (and are) professors at the University of Science and Technology of China, in Hefei—her mother in mechanical engineering and her father in fluid dynamics. During the 1970s and 80s, when Zhuang was a child, faculty members shared offices, so conversations with Ph.D. students occurred at home to avoid disturbing colleagues. “I didn’t fully understand what they were discussing, but it looked like they were very excited about finding something new,” she says. “That looked like a fun thing to do. Starting from grade school, I thought, ‘I want to be a professor.’”

In middle school, she began receiving formal instruction about Newton’s laws of motion. “If you know a little about the basics, everything falls out in a straightforward way,” she says. In contrast, Chinese language and literature classes required her “to learn an entire essay, word for word. We had to memorize and recite. In physics, I didn’t have to remember anything. I just had to provide my reasoning.” Her professional goal “switched from just professor to physics professor,” she says.

The pre-college school curriculum offered little biology education, and that topic eluded her until later. “The human body was optional,” she says. “The teachers did not want us to be pre-exposed to some of the body parts. They found it difficult to teach.”

For university studies, she majored in physics at the prestigious institution where her parents taught, and then she earned her Ph.D. at the University of California, Berkeley, in the field of optical spectroscopy with Yuen-Ron Shen. She joined Steven Chu’s lab at Stanford University as a postdoctoral fellow. Chu encouraged her to develop physics tools for biology.

Although Zhuang initially thought that biology relied on “remembering a lot of facts,” she soon realized that the approach to biological research was similar to that in physics. “You apply the same logical thinking and build your experiment to tackle problems, to hunt and discover new treasures.”

Zhuang’s training in a different domain helped her peer into living things with clear eyes and an unbiased mind, she says. Because she did not specialize in a biological discipline, she had no desire to “keep going in that direction,” she says. “But I’m probably not that kind of a person anyway. I keep getting interested in new systems that I’ve not gotten exposed to.”

Chu urged Zhuang to study whatever captivated her, and she took aim at a wall that was obscuring scientists’ view of detailed mechanisms. Conventional techniques analyze populations of molecules, and that strategy muddies crucial information. Molecules move as they perform their jobs, so looking at large numbers of them that act asynchronously creates a blur—a sort of average—rather than a clear picture of what any individual is doing. By labeling RNA and proteins with pairs of interacting fluorescent molecules that turn on and off as the distance between them fluctuates, she and other members of the Chu lab began watching single molecule gymnastics in real time under a microscope.

The ability to zoom in on previously imperceptible events hooked Zhuang. “I love this direct visualization approach,” she says. “Throughout my scientific life, I’ve invented new tools to see better.”

In 2001, she joined the faculty at Harvard University. As an independent investigator there, she decided to study biological molecules in a physiological setting—the inside of cells. In this system, she did not have the “luxury” of spreading them out to visualize each one separately, as she previously had done. “It’s crowded inside a cell,” she says. “I realized there’s this major limitation, and then I had a desire to overcome that barrier.”

Even the best microscope lens cannot focus light to an infinitely small spot. Rather, the tightest beams illuminate about 200 nanometers. Similarly, each fluorescently tagged molecule emits light to form an image that is about 200 nanometers wide. This so-called diffraction limit makes it impossible to discern molecules that are less than that distance apart. Because biological molecules are about 10-100 times smaller than 200 nanometers and lie close together, neighbors emanate overlapping signals that blend into one another. With these constraints, attempting to figure out what each molecule is doing is like trying to watch a football game from high above the earth, when the smallest area you can see is the entire field. Individual players are invisible, and viewers cannot possibly witness a kick or a pass.

Zhuang wanted to make each molecule appear crisp. She devised a strategy by which she allowed each one to shine at a different time. Toward that end, she labeled her molecule of interest with dye molecules whose fluorescence, her lab discovered, could be switched on and off. Then she gently activated the dyes so that only a small proportion of molecules glowed. Consequently, the resulting spots did not overlap, so she could pinpoint each molecule’s position. Each time she repeated this procedure, she detected and located a different subset of molecules. Then she combined the data to assemble an image at about 20 nm resolution—ten times smaller than the diffraction limit. She subsequently honed resolution ten times more, all the way to the molecular scale.

Her 2006 description of this method—sub-diffraction-limit imaging by stochastic optical reconstruction microscopy (STORM) —was one of the first papers to demonstrate super resolution imaging by sequentially lighting and darkening single molecules. Sixteen months later, Zhuang reported that she had extended STORM into three dimensions.

In 2013, she applied 3D STORM to discover a previously unknown framework in axons, the long fibers that conduct neuronal messages. The structure recruits and anchors many molecules that interact with one another to foster signaling that promotes neuronal growth and communication. This and related work opened a new area of neurobiology and displayed the power of STORM to divulge an unrecognized cellular apparatus.

Zhuang continued barreling through barriers. She began dreaming up ways to examine with exquisite precision sizable and complex systems of gene activity at the whole genome level. Thousands of gene products, the proteins they encode, make cells run properly and bestow their tissue identities—liver, nerve, and so on. The template for each protein, mRNA, has to appear not only at the right times and in the right quantities, but also in the right places.

Zhuang recognized another opportunity to blast through limitations imposed by existing approaches. Available protocols to gauge amounts of mRNA while also locating it inside cells analyzed a few mRNAs simultaneously in individual cells; they could not generate quantitative and spatial information about the activity of large numbers of genes. “You could get the pieces,” Zhuang says, “but you couldn’t get the whole picture. For that, we need to be able to image at the genome scale.”

The number of distinct fluorescent dyes seemed to limit the possibilities, but again she triumphed. In 2015, she published a technology she’d devised to simultaneously measure and map thousands of genes’ mRNAs inside intact cells. The genetic signatures that this method—multiplexed error-robust fluorescence in situ hybridization (MERFISH)—produces can help scientists identify unknown cells and determine spatial relationships among different types of cells in native tissue. Furthermore, mRNAs whose products collaborate on certain shared physiological processes hang out together. An undefined mRNA’s presence in such clusters might point toward its duties through guilt by association.

Zhuang has directed MERFISH toward a brain region that controls numerous essential functions. Scientists knew that the structure regulates temperature, sleep, thirst, parenting, sexual activity, and other social behaviors, but its cellular components, their organization, and their individual roles were largely mysterious. Zhuang and colleagues imaged more than a million mouse cells in this brain region, inventoried the types of neurons present, and outlined their arrangements relative to one another. The researchers then determined which neurons fired when they allowed the rodents to mate or spurred parenting responses by exposing them to pups. These experiments showed that distinct sets of cells spark while engaging in each behavior, and the team is continuing to tease apart circuits that control related, but separate, activities.

Through these contributions and a multitude of others, Zhuang has relentlessly imagined, designed, and pioneered tactics that reveal unprecedented details of tissues, cells, and the molecules they contain. “If you invent new technologies,” she says, “you see things no one has seen before.”

Author: Evelyn Strauss, Ph.D.